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Penn AH, Falabella M, Sanchez A, Hernandez O, McFadden K, Hutcheson J. 25% HUMAN SERUM ALBUMIN IMPROVES HEMODYNAMICS AND PREVENTS THE NEED FOR NEARLY ALL PREHOSPITAL RESUSCITATION IN A RAT ( RATTUS NORVEGICUS ) MODEL OF TRAUMA AND HEMORRHAGE. Shock 2024; 61:869-876. [PMID: 38319752 DOI: 10.1097/shk.0000000000002313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
ABSTRACT Combat casualty care can be complicated by transport times exceeding the "golden hour," with intervention and resuscitation limited to what the medic can carry. Pharmaceutical albumin comes highly saturated with nonesterified fatty acids (NEFAs). We recently showed that treatment with 25% bovine serum albumin (BSA) loaded with oleic acid, but not NEFA-free BSA, improved survival for hours after severe hemorrhage and often eliminated the need for resuscitation in rats. However, it was unknown whether pharmaceutical albumin, derived from human sources and loaded with caprylic acid (CA), would have the same benefits. We compared adjunct treatment with oleic acid-saturated BSA, CA-saturated BSA, pharmaceutical human serum albumin, or a no-albumin control in a similar rat hemorrhagic shock model to determine whether the three NEFA-albumin groups provided the same benefits relative to control. We found almost no significant differences among the NEFA-albumin groups in any measure. Mortality in controls was too low to allow for detection of improvement in survival, but NEFA-albumin groups had significantly improved hemodynamics, lactate clearance, and greatly reduced fluid requirements compared with controls. Contrary to expectations of "dehydration," 25% albumins shifted little additional fluid into the vasculature. Rather, they restored protein to the autotransfusion fluid. Nonesterified fatty acids-albumin did not worsen lung permeability, but we observed a loss of circulating protein suggesting it may have increased overall vascular permeability. Our findings suggest that, though imperfect, 25% human serum albumin could be a solution for resuscitation in austere conditions requiring prolonged field care.
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Affiliation(s)
- Alexander H Penn
- Defense Health Agency, United States Air Force 59th Medical Wing, Surgical and Technological Advancements for Traumatic Injury in Combat (STATIC), JBSA-Lackland, Texas
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Barth H, Worek F, Steinritz D, Papatheodorou P, Huber-Lang M. Trauma-toxicology: concepts, causes, complications. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2935-2948. [PMID: 37999755 PMCID: PMC11074020 DOI: 10.1007/s00210-023-02845-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
Trauma and toxic substances are connected in several aspects. On the one hand, toxic substances can be the reason for traumatic injuries in the context of accidental or violent and criminal circumstances. Examples for the first scenario is the release of toxic gases, chemicals, and particles during house fires, and for the second scenario, the use of chemical or biological weapons in the context of terroristic activities. Toxic substances can cause or enhance severe, life-threatening trauma, as described in this review for various chemical warfare, by inducing a tissue trauma accompanied by break down of important barriers in the body, such as the blood-air or the blood-gut barriers. This in turn initiates a "vicious circle" as the contribution of inflammatory responses to the traumatic damage enhances the macro- and micro-barrier breakdown and often results in fatal outcome. The development of sophisticated methods for detection and identification of toxic substances as well as the special treatment of the intoxicated trauma patient is summarized in this review. Moreover, some highly toxic substances, such as the protein toxins from the pathogenic bacterium Clostridioides (C.) difficile, cause severe post-traumatic complications which significantly worsens the outcome of hospitalized patients, in particular in multiply injured trauma patients. Therefore, novel pharmacological options for the treatment of such patients are necessarily needed and one promising strategy might be the neutralization of the toxins that cause the disease. This review summarizes recent findings on the molecular and cellular mechanisms of toxic chemicals and bacterial toxins that contribute to barrier breakdown in the human body as wells pharmacological options for treatment, in particular in the context of intoxicated trauma patients. "trauma-toxicology" comprises concepts regrading basic research, development of novel pharmacological/therapeutic options and clinical aspects in the complex interplay and "vicious circle" of severe tissue trauma, barrier breakdown, pathogen and toxin exposure, tissue damage, and subsequent clinical complications.
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Affiliation(s)
- Holger Barth
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany.
| | - Franz Worek
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
| | - Dirk Steinritz
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany
| | - Panagiotis Papatheodorou
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, University of Ulm Medical Center, Ulm, Germany.
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Li L, Jiang H, Qiu Z, Wang Z, Hu Z. EFFECT OF MIR-21-3P ON INTESTINAL INJURY IN RATS WITH TRAUMATIC HEMORRHAGIC SHOCK RESUSCITATED WITH THE SODIUM BICARBONATE RINGER'S SOLUTION. Shock 2024; 61:776-782. [PMID: 38517274 DOI: 10.1097/shk.0000000000002297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2024]
Abstract
ABSTRACT Background : This study aims to determine the impact and mechanism of miR-21-3p on intestinal injury and intestinal glycocalyx during fluid resuscitation in traumatic hemorrhagic shock (THS), and the different impacts of sodium lactate Ringer's solution (LRS) and sodium bicarbonate Ringer's solution (BRS) for resuscitation on intestinal damage. Methods : A rat model of THS was induced by hemorrhage from the left femur fracture. The pathological changes of intestinal tissues and glycocalyx structure were observed by hematoxylin-eosin staining and transmission electron microscope. MiR-21-3p expression in intestinal tissues was detected by real-time quantitative polymerase chain reaction. The expression of glycocalyx-, cell junction-, and PI3K/Akt/NF-κB signaling pathway-related proteins was analyzed by western blot. Results : MiR-21-3p expression was increased in THS rats, which was suppressed by resuscitation with BRS. BRS or LRS aggravated the intestinal injury and damaged intestinal glycocalyx in THS rats. The expression of SDC-1, HPA, β-catenin, MMP2, and MMP9 was upregulated, the expression of E-cad was downregulated, and the PI3K/Akt/NF-κB signaling pathway was activated in THS rats, which were further aggravated by BRS or LRS. The adverse effect of LRS was more serious than BRS. MiR-21-3p overexpression deteriorated the injury of intestinal tissues and intestinal glycocalyx; increased the expression of SDC-1, HPA, β-catenin, MMP2, and MMP9 while decreasing E-cad expression; and activated the PI3K/Akt/NF-κB signaling pathway in BRS-resuscitated THS rats. Conclusion : MiR-21-3p aggravated intestinal tissue injury and intestinal glycocalyx damage through activating PI3K/Akt/NF-κB signaling pathway in rats with THS resuscitated with BRS.
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Affiliation(s)
| | | | | | - Zhenjie Wang
- Department of Emergency Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
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Abenavoli L, Scarpellini E, Paravati MR, Scarlata GGM, Boccuto L, Tilocca B, Roncada P, Luzza F. Gut Microbiota and Critically Ill Patients: Immunity and Its Modulation via Probiotics and Immunonutrition. Nutrients 2023; 15:3569. [PMID: 37630759 PMCID: PMC10459644 DOI: 10.3390/nu15163569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Critically ill patients have a hyper-inflammatory response against various offending injuries that can result in tissue damage, organ failure, and fatal prognosis. The origin of this detrimental, uncontrolled inflammatory cascade can be found also within our gut. In detail, one of the main actors is our gut microbiota with its imbalance, namely gut dysbiosis: learning about the microbiota's dysfunction and pathophysiology in the frame of critical patients is of crucial and emerging importance in the management of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Multiple pieces of evidence indicate that the bacteria that populate our gut efficiently modulate the immune response. Treatment and pretreatment with probiotics have shown promising preliminary results to attenuate systemic inflammation, especially in postoperative infections and ventilation performance. Finally, it is emerging how immunonutrition may exert a possible impact on the health status of patients in intensive care. Thus, this manuscript reviews evidence from the literature on gut microbiota composition, its derangement in critically ill patients, its pathophysiological role, and the described and emerging opportunities arising from its modulation.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (G.G.M.S.); (B.T.); (P.R.); (F.L.)
| | - Emidio Scarpellini
- Translationeel Onderzoek van Gastro-Enterologische Aandoeningen (T.A.R.G.I.D.), Gasthuisberg University 11 Hospital, KU Leuven, Herestraat 49, 3000 Leuven, Belgium;
| | - Maria Rosaria Paravati
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (G.G.M.S.); (B.T.); (P.R.); (F.L.)
| | - Giuseppe Guido Maria Scarlata
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (G.G.M.S.); (B.T.); (P.R.); (F.L.)
| | - Luigi Boccuto
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, SC 29634, USA;
- School of Health Research, Clemson University, Clemson, SC 29634, USA
| | - Bruno Tilocca
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (G.G.M.S.); (B.T.); (P.R.); (F.L.)
| | - Paola Roncada
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (G.G.M.S.); (B.T.); (P.R.); (F.L.)
| | - Francesco Luzza
- Department of Health Sciences, University “Magna Graecia”, 88100 Catanzaro, Italy; (M.R.P.); (G.G.M.S.); (B.T.); (P.R.); (F.L.)
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Senda A, Kojima M, Watanabe A, Kobayashi T, Morishita K, Aiboshi J, Otomo Y. Profiles of lipid, protein and microRNA expression in exosomes derived from intestinal epithelial cells after ischemia-reperfusion injury in a cellular hypoxia model. PLoS One 2023; 18:e0283702. [PMID: 36989330 PMCID: PMC10058167 DOI: 10.1371/journal.pone.0283702] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Intestinal ischemia-reperfusion injury leads to proinflammatory responses via gut-derived mediators, and accumulating evidence suggests that exosomes secreted by intestinal epithelial cells are involved in the development of systemic inflammation. Studies have reported changes in protein, lipid, and microRNA (miRNA) expression; however, considering the different experimental conditions, information on the relationships among these biomolecules remains insufficient. The aim of this study was to elucidate the multiple changes that simultaneously occur in exosomes after ischemic stimulation. Here, differentiated human intestinal Caco-2 cells were exposed to 95% air (normoxia group) or 5% O2 (hypoxia group) for 6 h. Cells in each group were subsequently incubated for 24 h in an atmosphere of 5% CO2 plus 95% air. The conditioned medium of each group was collected for isolating intestinal epithelial cell-derived exosomes. Together with proteome analyses, lipid analyses, and miRNA quantification, biological functional assays were performed using monocytic NF-κB reporter cells. Lipid metabolism-related protein expression was upregulated, miRNA levels were slightly altered, and unsaturated fatty acid-containing lysophosphatidylcholine concentration increased after hypoxia and reoxygenation injury; this suggested that the changes in exosomal components associated with ischemia-reperfusion injury activates inflammation, including the NF-κB pathway. This study elucidated the multiple changes that co-occur in exosomes after ischemic stimulation and partially clarified the mechanism underlying exosome-mediated inflammation after intestinal ischemic recanalization.
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Affiliation(s)
- Atsushi Senda
- Department of Acute Critical Care and Disaster Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Mitsuaki Kojima
- Department of Acute Critical Care and Disaster Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
- Emergency and Critical Care Center, Tokyo Women's Medical University Adachi Medical Center, Adachi-ku, Tokyo, Japan
| | - Arisa Watanabe
- Department of Biological Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Bunkyo-ku, Tokyo, Japan
| | - Tetsuyuki Kobayashi
- Department of Biological Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Bunkyo-ku, Tokyo, Japan
| | - Koji Morishita
- Department of Acute Critical Care and Disaster Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Junichi Aiboshi
- Department of Emergency and Critical Care Medicine, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan
| | - Yasuhiro Otomo
- Department of Acute Critical Care and Disaster Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
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Quan Y, Yin Z, Chen S, Lang J, Han L, Yi J, Zhang L, Yue Q, Tian W, Chen P, Du S, Wang J, Dai Y, Hua H, Zeng J, Li L, Zhao J. The gut-lung axis: Gut microbiota changes associated with pulmonary fibrosis in mouse models induced by bleomycin. Front Pharmacol 2022; 13:985223. [PMID: 36249808 PMCID: PMC9561135 DOI: 10.3389/fphar.2022.985223] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/22/2022] [Indexed: 12/02/2022] Open
Abstract
The main objective of this study was to investigate the alterations in the gut microbiota (GM) of pulmonary fibrosis (PF) mice induced by bleomycin (BLM) with its underlying mechanisms. BLM was docked with the targets of TGF-β/SMAD and caspase-3 pathways using the molecular docking technique. HE staining and Masson staining were applied to observe the histopathological changes in the pulmonary tissues. Detection of the apoptotic signals was conducted by flow cytometry and TUNEL staining. The mRNA expression of targets involved in the TGF-β/SMAD and caspase-3 signaling pathways in lungs was determined by qPCR. Immunohistochemistry (IHC) assay was used to detect the expression levels of cleaved caspase-3 and BAX proteins in mice lung tissues. 16S rDNA sequencing analysis was used to investigate the changes of GM in the fecal samples of mice in each group. The results showed that the apoptosis rate of pulmonary cells in the BLM group distinctly increased, with the expression levels of crucial target pro-apoptotic gene caspase-3, BAX with the corresponding protein, cleaved caspase-3, BAX were apparently elevated. This was accompanied by a significant increase in pro-fibrotic targets level such as TGF-β, fibronectin, collagen I, and collagen III. The mechanisms of PF induced by BLM were related to apoptosis of lung tissue cells such as alveolar epithelial cells and destroyed alveolar structure and excessive production of extracellular matrix (ECM), which may be bound up with activating TGF-β/SMAD and caspase-3 pathways. As for the GM, it was found that, after BLM induced PF in mice, the micro ecological balance of the GM was destroyed; the distance of PCo1 and Pco2 was significantly elongated, and the relative abundance of some intestinal probiotics like Catenibacterium and Lactobacillus (L. johnsonii and L. gasseri) dramatically lowered while the relative abundance of Verrucomicrobiales and Enterobacteriales substantially increased. Therefore, GM changes associated with PF in mouse models induced by BLM and the concept of "gut-lung axis" might provide an optional therapeutic strategy for PF.
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Affiliation(s)
- Yunyun Quan
- Department of Pharmacognosy, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Zhujun Yin
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Shilong Chen
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Jirui Lang
- Department of Pharmacognosy, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Liyang Han
- Department of Pharmacognosy, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jing Yi
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Lu Zhang
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Qianhua Yue
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Weiwei Tian
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Ping Chen
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Shenglin Du
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Jianbo Wang
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Ying Dai
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Hua Hua
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Jin Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Li Li
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan, China
| | - Junning Zhao
- Department of Pharmacognosy, West China School of Pharmacy, Sichuan University, Chengdu, China
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Schäfer TV, Vakunenkova OA, Ivnitsky JJ, Golovko AI. Gut Barrier in Critical States of the Body. BIOLOGY BULLETIN REVIEWS 2022. [PMCID: PMC9297268 DOI: 10.1134/s2079086422040077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The intestinal barrier (IB) is a system of diffusion barriers separating the intestinal chyme and blood. The aim of the review is to identify the role of IB dysfunction in the formation of critical states of the body and to substantiate ways to prevent these states. Toxic substances produced by normal intestinal microflora are characterized. The involvement of endotoxin and ammonia in the pathogenesis of sepsis, acute circulatory disorders, secondary acute pulmonary lesions, and acute cerebral insufficiency is shown. Approaches to protect the IB in critical states of the body are proposed.
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Affiliation(s)
- T. V. Schäfer
- State Scientific Research and Testing Institute of Military Medicine, St. Petersburg, Russia
| | - O. A. Vakunenkova
- Golikov Scientific and Clinical Center of Toxicology, St. Petersburg, Russia
| | - Ju. Ju. Ivnitsky
- Golikov Scientific and Clinical Center of Toxicology, St. Petersburg, Russia
| | - A. I. Golovko
- Golikov Scientific and Clinical Center of Toxicology, St. Petersburg, Russia
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Ivnitsky JJ, Schäfer TV, Rejniuk VL, Vakunenkova OA. Secondary Dysfunction of the Intestinal Barrier in the Pathogenesis of Complications of Acute Poisoning. J EVOL BIOCHEM PHYS+ 2022; 58:1075-1098. [PMID: 36061072 PMCID: PMC9420239 DOI: 10.1134/s0022093022040123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 11/22/2022]
Abstract
The last decade has been marked by an exponential increase
in the number of publications on the physiological role of the normal
human gut microbiota. The idea of a symbiotic relationship between
the human organism and normal microbiota of its gastrointestinal
tract has been firmly established as an integral part of the current
biomedical paradigm. However, the type of this symbiosis varies
from mutualism to parasitism and depends on the functional state
of the host organism. Damage caused to the organism by external
agents can lead to the emergence of conditionally pathogenic properties
in the normal gut microbiota, mediated by humoral factors and affecting
the outcome of exogenous exposure. Among the substances produced
by symbiotic microbiota, there are an indefinite number of compounds
with systemic toxicity. Some occur in the intestinal chyme in potentially
lethal amounts in the case they enter the bloodstream quickly. The quick
entry of potential toxicants is prevented by the intestinal barrier
(IB), a set of structural elements separating the intestinal chyme
from the blood. Hypothetically, severe damage to the IB caused by
exogenous toxicants can trigger a leakage and subsequent systemic
redistribution of toxic substances of bacterial origin. Until recently,
the impact of such a redistribution on the outcome of acute exogenous
poisoning remained outside the view of toxicology. The present review
addresses causal relationships between the secondary dysfunction
of the IB and complications of acute poisoning. We characterize
acute systemic toxicity of such waste products of the normal gut microflora
as ammonia and endotoxins, and demonstrate their involvement in
the formation of such complications of acute poisoning as shock,
sepsis, cerebral insufficiency and secondary lung injuries. The
principles of assessing the functional state of the IB and the approaches
to its protection in acute poisoning are briefly considered.
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Affiliation(s)
- Ju. Ju. Ivnitsky
- Golikov Research Clinical Center of Toxicology, Federal Medical Biological Agency, St. Petersburg, Russia
| | - T. V. Schäfer
- State Scientific Research Test Institute of Military Medicine, Ministry of Defense of the Russian Federation, St. Petersburg, Russia
| | - V. L. Rejniuk
- Golikov Research Clinical Center of Toxicology, Federal Medical Biological Agency, St. Petersburg, Russia
| | - O. A. Vakunenkova
- Golikov Research Clinical Center of Toxicology, Federal Medical Biological Agency, St. Petersburg, Russia
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Lin J, Tan B, Li Y, Feng H, Chen Y. Sepsis-Exacerbated Brain Dysfunction After Intracerebral Hemorrhage. Front Cell Neurosci 2022; 15:819182. [PMID: 35126060 PMCID: PMC8814659 DOI: 10.3389/fncel.2021.819182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 12/27/2021] [Indexed: 12/28/2022] Open
Abstract
Sepsis susceptibility is significantly increased in patients with intracerebral hemorrhage (ICH), owing to immunosuppression and intestinal microbiota dysbiosis. To date, ICH with sepsis occurrence is still difficult for clinicians to deal with, and the mortality, as well as long-term cognitive disability, is still increasing. Actually, intracerebral hemorrhage and sepsis are mutually exacerbated via similar pathophysiological mechanisms, mainly consisting of systemic inflammation and circulatory dysfunction. The main consequence of these two processes is neural dysfunction and multiple organ damages, notably, via oxidative stress and neurotoxic mediation under the mediation of central nervous system activation and blood-brain barrier disruption. Besides, the comorbidity-induced multiple organ damages will produce numerous damage-associated molecular patterns and consequently exacerbate the severity of the disease. At present, the prospective views are about operating artificial restriction for the peripheral immune system and achieving cross-tolerance among organs via altering immune cell composition to reduce inflammatory damage.
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Affiliation(s)
- Jie Lin
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
| | - Binbin Tan
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
| | - Yuhong Li
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
| | - Hua Feng
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Hua Feng, ;
| | - Yujie Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University, Army Medical University, Chongqing, China
- *Correspondence: Yujie Chen, ;
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10
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Conner J, Lammers D, Holtestaul T, Jones I, Kuckelman J, Letson H, Dobson G, Eckert M, Bingham J. Combatting ischemia reperfusion injury from resuscitative endovascular balloon occlusion of the aorta using adenosine, lidocaine and magnesium: A pilot study. J Trauma Acute Care Surg 2021; 91:995-1001. [PMID: 34446655 DOI: 10.1097/ta.0000000000003388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Resuscitative endovascular balloon occlusion of the aorta (REBOA), a minimally invasive alternative to resuscitative thoracotomy, has been associated with significant ischemia reperfusion injury (IRI). Resuscitation strategies using adenosine, lidocaine, and magnesium (ALM) have been shown to mitigate similar inflammatory responses in hemorrhagic and septic shock models. This study examined the effects of ALM on REBOA-associated IRI using a porcine model. METHODS Animals underwent a 20% controlled hemorrhage followed by 30 minutes of supraceliac balloon occlusion. They were assigned to one of four groups: control (n = 5), 4-hour ALM infusion starting at occlusion, 2-hour (n = 5) and 4-hour (n = 5) interventional ALM infusions starting at reperfusion. Adenosine, lidocaine, and magnesium cohorts received a posthemorrhage ALM bolus followed by their respective ALM infusion. Primary outcomes for the study assessed physiologic and hemodynamic parameters. RESULTS Adenosine, lidocaine, and magnesium infusion after reperfusion cohorts demonstrated a significant improvement in lactate, base deficit, and pH in the first hour following systemic reperfusion. At study endpoint, continuous ALM infusion initiated after reperfusion over 4 hours resulted in an overall improved lactate clearance when compared with the 2-hour and control cohorts. No differences in hemodynamic parameters were noted between ALM cohorts and controls. CONCLUSION Adenosine, lidocaine, and magnesium may prove beneficial in mitigating the inflammatory response seen from REBOA-associated IRI as evidenced by physiologic improvements early during resuscitation. Despite this, further refinement should be sought to optimize treatment strategies.
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Affiliation(s)
- Jeff Conner
- From the Madigan Army Medical Center (J.C., D.L., T.H., I.J., J.K., M.E., J.B.), Tacoma, Washington; Heart Trauma and Sepsis Research Laboratory, College of Medicine and Dentistry (H.L., G.D.), James Cook University, Townsville, Queensland, Australia; and Department of Surgery (M.E.), University of North Carolina, Chapel Hill, North Carolina
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11
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Differential Effect of Light and Dark Period Sleep Fragmentation on Composition of Gut Microbiome and Inflammation in Mice. Life (Basel) 2021; 11:life11121283. [PMID: 34947814 PMCID: PMC8709399 DOI: 10.3390/life11121283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/17/2022] Open
Abstract
Bi-directional interactions amongst the gut microbiota, immune system, and brain function are thought to be critical mediators of health and disease. The role sleep plays in mediating these interactions is not known. We assessed the effects of sleep fragmentation (SF) on the microbiota–gut–brain axis. Male C57BL/6NCrl mice (4 to 5 per cage, fed standard lab chow) experienced SF via mechanical stimulation at 2 min intervals during the light (SF) and dark (DD, dark disturbances) periods. Home cage (HC) controls were undisturbed. After 10 days, fecal samples were collected at light onset, midday, light offset, and midnight. Samples were also collected after 10 days without SF. Subsequently, the mice were randomized across groups and allowed 20 additional days of recovery followed by 10 days of SF or DD. To assess effects on the microbiota, 16S rRNA sequencing was used, and mesenteric lymph nodes (MLNs) and cortex and medial prefrontal cortex were analyzed using cytokine arrays. SF and DD produced significant alterations in the microbiota compared to HC, and DD had greater impact than SF on some organisms. SF produced marked suppression in MLNs of chemokines that regulate inflammation (CCL3, CCL4 and their receptor CCR5) and maintain the immune mucosal barrier (Cxcl13) at the same time that cortical cytokines (IL-33) indicated neuroinflammation. DD effects on immune responses were similar to HC. These data suggest that SF alters the microbiome and suppresses mucosal immunity at the same time that mediators of brain inflammation are upregulated. The translational implications for potential application to clinical care are compelling.
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12
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Wu J, Yin Y, Qin M, Li K, Liu F, Zhou X, Song X, Li B. Vagus Nerve Stimulation Protects Enterocyte Glycocalyx After Hemorrhagic Shock Via the Cholinergic Anti-Inflammatory Pathway. Shock 2021; 56:832-839. [PMID: 33927140 PMCID: PMC8519159 DOI: 10.1097/shk.0000000000001791] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 04/08/2021] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Electrical vagal nerve stimulation is known to decrease gut permeability and alleviate gut injury caused by traumatic hemorrhagic shock. However, the specific mechanism of action remains unclear. Glycocalyx, located on the surface of the intestinal epithelium, is associated with the buildup of the intestinal barrier. Therefore, the goal of our study was to explore whether vagal nerve stimulation affects enterocyte glycocalyx, gut permeability, gut injury, and remote lung injury. MATERIALS AND METHODS Male Sprague Dawley rats were anesthetized and their cervical nerves were exposed. The rats underwent traumatic hemorrhagic shock (with maintenance of mean arterial pressure of 30-35 mmHg for 60 min) with fluid resuscitation. Vagal nerve stimulation was added to two cohorts of animals before fluid resuscitation, and one of them was injected with methyllycaconitine to block the cholinergic anti-inflammatory pathway. Intestinal epithelial glycocalyx was detected using immunofluorescence. Intestinal permeability, the degree of gut and lung injury, and inflammation factors were also assessed. RESULTS Vagal nerve stimulation alleviated the damage to the intestinal epithelial glycocalyx and decreased intestinal permeability by 43% compared with the shock/resuscitation phase (P < 0.05). Methyllycaconitine partly eliminated the effects of vagal nerve stimulation on the intestinal epithelial glycocalyx (P < 0.05). Vagal nerve stimulation protected against traumatic hemorrhagic shock/fluid resuscitation-induced gut and lung injury, and some inflammatory factor levels in the gut and lung tissue were downregulated after vagal nerve stimulation (P < 0.05). CONCLUSIONS Vagal nerve stimulation could relieve traumatic hemorrhagic shock/fluid resuscitation-induced intestinal epithelial glycocalyx damage via the cholinergic anti-inflammatory pathway.
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Affiliation(s)
- Juan Wu
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yushuang Yin
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Mingzhe Qin
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
| | - Kun Li
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
| | - Fang Liu
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
| | - Xiang Zhou
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
| | - Xiaoyang Song
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
| | - Bixi Li
- Department of Anesthesiology, General Hospital of Central Theater Command of PLA, Wuhan, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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13
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Nakatsutsumi K, Morishita K, Yagi M, Doki S, Watanabe A, Ikegami N, Kobayashi T, Kojima M, Senda A, Yamamoto K, Aiboshi J, Coimbra R, Otomo Y. Vagus nerve stimulation modulates arachidonic acid production in the mesenteric lymph following intestinal ischemia-reperfusion injury. J Trauma Acute Care Surg 2021; 91:700-707. [PMID: 34238858 DOI: 10.1097/ta.0000000000003345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Inflammatory lipid mediators in mesenteric lymph (ML), including arachidonic acid (AA), are considered to play an important role in the pathogenesis of multiple-organ dysfunction after hemorrhagic shock. A previous study suggested that vagus nerve stimulation (VNS) could relieve shock-induced gut injury and abrogate ML toxicity, resulting in the prevention of multiple-organ dysfunction. However, the detailed mechanism of VNS in lymph toxicity remains unclear. The study aimed to investigate the relationship between VNS and inflammatory lipid mediators in ML. METHODS Male Sprague-Dawley rats underwent laparotomy and superior mesenteric artery obstruction (SMAO) for 60 minutes to induce intestinal ischemia followed by reperfusion and observation. The ML duct was cannulated, and ML samples were obtained both before and after SMAO. The distal ileum was removed at the end of the observation period. In one group of animals, VNS was performed from 10 minutes before 10 minutes after SMAO (5 V, 0.5 Hz). Liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of AA was performed for each ML sample. The biological activity of ML was examined using a monocyte nuclear factor κ-light-chain-enhancer of activated B cells activation assay. Western blotting of phospholipase A2 group IIA (PLA2-IIA) was also performed for ML and ileum samples. RESULTS Vagus nerve stimulation relieved the SMAO-induced histological gut injury. The concentration of AA and level of nuclear factor κ-light-chain-enhancer of activated B cells activation in ML increased significantly after SMAO, whereas VNS prevented these responses. Western blotting showed PLA2-IIA expression in the ML and ileum after SMAO; however, the appearance of PLA2-IIA band was remarkably decreased in the samples from VNS-treated animals. CONCLUSION The results suggested that VNS could relieve gut injury induced by SMAO and decrease the production of AA in ML by altering PLA2-IIA expression in the gut and ML.
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Affiliation(s)
- Keita Nakatsutsumi
- From the Department of Acute Critical Care and Disaster Medicine (K.N., Y.O.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University; Department of Acute Critical Care and Disaster Medicine (K.N., K.M., A.S., J.A., Y.O.), Tokyo Medical and Dental University Hospital of Medicine; Department of Biological Sciences (S.D., A.W., N.I., T.K.), Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo; Emergency Medicine and Acute Care Surgery (M.Y.), Matsudo City General Hospital, Chiba; Emergency and Critical Care Center (M.K.), Tokyo Women's Medical University Medical Center East; Department of Comprehensive Pathology (K.Y.), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; and Department of Surgery (R.C.), Riverside University Health System Medical Center, Loma Linda University School of Medicine, Loma Linda, California
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14
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Escott ABJ, Hong J, Connor BN, Phang KL, Holden AH, Phillips ARJ, Windsor JA. Sampling Thoracic Duct Lymph After Esophagectomy: A Pilot Study Investigating the "Gut-Lymph" Concept. Lymphat Res Biol 2021; 20:260-274. [PMID: 34582739 DOI: 10.1089/lrb.2019.0037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Introduction: Gut-lymph in animal models of acute disease is altered by intestinal ischemia and contributes to the development of systemic inflammation and organ dysfunction. Investigating gut-lymph in humans is hampered difficulty in accessing the thoracic duct (TD) for lymph sampling. The aims of this study were to develop and pilot a technique of intraoperative TD cannulation with delayed embolization to serially measure TD lymph pressure, flow, and composition (including markers of intestinal injury) during the early postoperative period and in response to enteral feeding and vasopressor treatment. Methods: A Seldinger technique was used for percutaneous TD cannulation during an Ivor Lewis esophagogastrectomy. Lymph flow rate and pressure were measured. TD lymph and plasma were sampled at 12 hourly intervals for up to 120 hours after surgery and before TD embolization. Biochemistry, lipids, cytokines, and markers of intestinal injury were measured before and after enteral feeding commenced at 36 hours. Results: Intraoperative TD cannulation was technically feasible in three of four patients. Delayed TD embolization was only successful in one of three patients, with two patients requiring a re-thoracotomy to treat chylothorax. Profound changes in TD composition, but not flow rate, occurred over time and in response to enteral feeding and vasopressors. TD lymph compared with plasma had significantly higher lipase (1.4-17 × ), interleukin-6 (8-108 × ), tumor necrosis factor-α (2.7-17 × ), d-lactate (0.3-23 × ), endotoxin (0.1-41 × ), and intestinal fatty acid binding protein (1.1-853 × ). Conclusions: Although TD cannulation and lymph sampling were successful, TD embolization failed in two of three patients. The composition of sampled TD lymph changed dramatically in response to enteral feeding, indicating intestinal ischemia that could be exacerbated by nonselective vasopressors. The higher concentration of proinflammatory cytokines and gut injury markers in TD lymph, compared with plasma, lends support to the gut-lymph concept.
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Affiliation(s)
| | - Jiwon Hong
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences and Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - Brigid Nancy Connor
- Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand
| | - Kian Liun Phang
- North Shore Hospital, Waitemata District Health Board, Auckland, New Zealand
| | - Andrew Hugh Holden
- Auckland City Hospital, Auckland District Health Board, Auckland, New Zealand
| | - Anthony Ronald John Phillips
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences and Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - John Albert Windsor
- Department of Surgery, Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
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15
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Shimizu K, Ojima M, Ogura H. Gut Microbiota and Probiotics/Synbiotics for Modulation of Immunity in Critically Ill Patients. Nutrients 2021; 13:nu13072439. [PMID: 34371948 PMCID: PMC8308693 DOI: 10.3390/nu13072439] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/24/2021] [Accepted: 07/10/2021] [Indexed: 12/26/2022] Open
Abstract
Patients suffering from critical illness have host inflammatory responses against injuries, such as infection and trauma, that can lead to tissue damage, organ failure, and death. Modulation of host immune response as well as infection and damage control are detrimental factors in the management of systemic inflammation. The gut is the motor of multiple organ failure following injury, and it is recognized that gut dysfunction is one of the causative factors of disease progression. The gut microbiota has a role in maintaining host immunity, and disruption of the gut microbiota might induce an immunosuppressive condition in critically ill patients. Treatment with probiotics and synbiotics has been reported to attenuate systemic inflammation by maintaining gut microbiota and to reduce postoperative infectious complications and ventilator-associated pneumonia. The administration of prophylactic probiotics/synbiotics could be an important treatment option for preventing infectious complications and modulating immunity. Further basic and clinical research is needed to promote intestinal therapies for critically ill patients.
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Abstract
PURPOSE OF REVIEW Existing data and all ICU nutrition guidelines emphasize enteral nutrition (EN) represents a primary therapy leading to both nutritional and non-nutritional benefits. Unfortunately, iatrogenic malnutrition and underfeeding is virtually ubiquitous in ICUs worldwide for prolonged periods post-ICU admission. Overcoming essential challenges to EN delivery requires addressing a range of real, and frequently propagated myths regarding EN delivery. RECENT FINDINGS Key recent data addresses perceived challenges to EN including: Adequately resuscitated patients on vasopressors can and likely should receive trophic early EN and this was recently associated with reduced mortality; Patients paralyzed with neuromuscular blocking agents can and should receive early EN as this was recently associated with reduced mortality/hospital length of stay; Proned patients can safely receive EN; All ICU nutrition delivery, including EN, should be objectively guided by indirect calorimetry (IC) measures. This is now possible with the new availability of a next-generation IC device. SUMMARY It is the essential implementation of this new evidence occurs to overcome real and perceived EN challenges. This data should lead to increased standardization/protocolization of ICU nutrition therapy to ensure personalized nutrition care delivering the right nutrition dose, in the right patient, at the right time to optimize clinical outcome.
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Affiliation(s)
- Paul E Wischmeyer
- Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA
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17
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Ma Y, Yang X, Chatterjee V, Wu MH, Yuan SY. The Gut-Lung Axis in Systemic Inflammation. Role of Mesenteric Lymph as a Conduit. Am J Respir Cell Mol Biol 2021; 64:19-28. [PMID: 32877613 DOI: 10.1165/rcmb.2020-0196tr] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Emerging evidence shows that after injury or infection, the mesenteric lymph acts as a conduit for gut-derived toxic factors to enter the blood circulation, causing systemic inflammation and acute lung injury. Neither the cellular and molecular identity of lymph factors nor their mechanisms of action have been well understood and thus have become a timely topic of investigation. This review will first provide a summary of background knowledge on gut barrier and mesenteric lymphatics, followed by a discussion focusing on the current understanding of potential injurious factors in the lymph and their mechanistic contributions to lung injury. We also examine lymph factors with antiinflammatory properties as well as the bidirectional nature of the gut-lung axis in inflammation.
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Affiliation(s)
- Yonggang Ma
- Department of Molecular Pharmacology and Physiology, and
| | - Xiaoyuan Yang
- Department of Molecular Pharmacology and Physiology, and
| | | | - Mack H Wu
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Sarah Y Yuan
- Department of Molecular Pharmacology and Physiology, and.,Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida
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18
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Burn Injury Induces Intestinal Inflammatory Response Mediated by Th17 in Burn-Primed Endotoxemic Mice. Int Surg 2020. [DOI: 10.9738/intsurg-d-18-00014.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective
This study aimed to elucidate the mechanism underlying the susceptibility to infection-related acute lung injury by focusing on the role of gut mucosal T-helper (Th) 17 cells that preferentially produce IL-17 with probiotics in a burn-primed endotoxemic mice model.
Methods
Mice were subjected to a 15% total body surface area third-degree burn. Survival from lethal lipopolysaccharide (LPS) administration (3 mg/kg) on 11th day post-burn was assessed in mice fed by chow with or without 1.2% Lactobacillus powder after burn injury. Lamina propria mononuclear cells were enzymatically isolated from the ileum removed on 11th day post-burn and incubated along with 1 μg/mL LPS or 10 μg/mL anti-CD3 antibody for 24 hours; subsequently, the following 7 cytokines were analyzed in the supernatant: IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17.
Results
Lactobacillus treatment post-burn injury markedly improved survival after lethal endotoxemia in burn-primed mice (64.3% versus 21.4%, P = 0.03). The production of proinflammatory cytokines such as TNF-α, IL-6, and IL-17 by lamina propria mononuclear T-lymphocytes and macrophages including Th17 response was augmented by burn injury but decreased with Lactobacillus treatment after burn injury.
Conclusions
Th17- and Th17-mediated inflammatory responses in the gut mucosa may play a vital role, which could be attenuated by Lactobacillus treatment, in survival of lethal endotoxemia in burn-primed mice.
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19
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Stewart RH. A Modern View of the Interstitial Space in Health and Disease. Front Vet Sci 2020; 7:609583. [PMID: 33251275 PMCID: PMC7674635 DOI: 10.3389/fvets.2020.609583] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022] Open
Abstract
Increases in the volume of the interstitial space are readily recognized clinically as interstitial edema formation in the loose connective tissue of skin, mucosa, and lung. However, the contents and the hydrostatic pressure of this interstitial fluid can be very difficult to determine even in experimental settings. These difficulties have long obscured what we are beginning to appreciate is a dynamic milieu that is subject to both intrinsic and extrinsic regulation. This review examines current concepts regarding regulation of interstitial volume, pressure, and flow and utilizes that background to address three major topics of interest that impact IV fluid administration. The first of these started with the discovery that excess dietary salt can be stored non-osmotically in the interstitial space with minimal impact on vascular volume and pressures. This led to the hypothesis that, along with the kidney, the interstitial space plays an active role in the long-term regulation of blood pressure. Second, it now appears that hypovolemic shock leads to systemic inflammatory response syndrome principally through the entry of digestive enzymes into the intestinal interstitial space and the subsequent progression of enzymes and inflammatory agents through the mesenteric lymphatic system to the general circulation. Lastly, current evidence strongly supports the non-intuitive view that the primary factor leading to inflammatory edema formation is a decrease in interstitial hydrostatic pressure that dramatically increases microvascular filtration.
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Affiliation(s)
- Randolph H Stewart
- Department of Veterinary Physiology and Pharmacology, Michael E. DeBakey Institute, Texas A&M University, College Station, TX, United States
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20
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Uzzan M, Corcos O, Martin JC, Treton X, Bouhnik Y. Why is SARS-CoV-2 infection more severe in obese men? The gut lymphatics - Lung axis hypothesis. Med Hypotheses 2020; 144:110023. [PMID: 32593832 PMCID: PMC7308746 DOI: 10.1016/j.mehy.2020.110023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
Abstract
Consistent observations report increased severity of SARS-CoV-2 infection in overweight men with cardiovascular factors. As the visceral fat possesses an intense immune activity, is involved in metabolic syndrome and is at the crossroad between the intestines, the systemic circulation and the lung, we hypothesized that it plays a major role in severe forms of SARS-CoV-2 infection. SARS-CoV2 presents the ability to infect epithelial cells of the respiratory tract as well as the intestinal tract. Several factors may increase intestinal permeability including direct enterocyte damage by SARS-CoV2, systemic inflammatory response syndrome (SIRS) and epithelial ischemia secondary to SARS-CoV2- associated endothelial dysfunction. This increase permeability further leads to translocation of microbial components such as MAMPs (microbial-associated molecular pattern), triggering an inflammatory immune response by TLR-expressing cells of the mesentery fat (mostly macrophages and adipocytes). The pro-inflammatory cytokines produced by the mesentery fat mediates systemic inflammation and aggravate acute respiratory distress syndrome (ARDS) through the mesenteric lymph drainage.
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Affiliation(s)
- Mathieu Uzzan
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France.
| | - Olivier Corcos
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France
| | - Jerome C Martin
- Université de Nantes, Inserm, CHU Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; CHU Nantes, Laboratoire d'Immunologie, Center for Immuno Monitoring Nantes-Atlantique (CIMNA), F-44000 Nantes, France
| | - Xavier Treton
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France
| | - Yoram Bouhnik
- Department of Gastroenterology, IBD and Nutritional Support, CHU Paris Nord-Val de Seine, Beaujon Hospital, Clichy, France
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21
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Mesenteric Lymph Duct Drainage Attenuates Lung Inflammatory Injury and Inhibits Endothelial Cell Apoptosis in Septic Rats. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3049302. [PMID: 33145344 PMCID: PMC7596461 DOI: 10.1155/2020/3049302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/06/2020] [Accepted: 08/13/2020] [Indexed: 01/19/2023]
Abstract
The present study was to investigate the effect of mesenteric lymph duct drainage on lung inflammatory response, histological alteration, and endothelial cell apoptosis in septic rats. Animals were randomly assigned into four groups: control, sham surgery, sepsis, and sepsis plus mesenteric lymph drainage. We used the colon ascendens stent peritonitis (CASP) procedure to induce the septic model in rats, and mesenteric lymph drainage was performed with a polyethylene (PE) catheter inserted into mesenteric lymphatic. The animals were sacrificed at the end of CASP in 6 h. The mRNA expression levels of inflammatory mediators were measured by qPCR, and the histologic damage were evaluated by the pathological score method. It was found that mesenteric lymph drainage significantly reduced the expression of TNF-α, IL-1β, and IL-6 mRNA in the lung. Pulmonary interstitial edema and infiltration of inflammatory cells were alleviated by mesenteric lymph drainage. Moreover, increased mRNA levels of TNF-α, IL-1β, IL-6 mRNA, and apoptotic rate were observed in PMVECs treated with septic lymph. These results indicate that mesenteric lymph duct drainage significantly attenuated lung inflammatory injury by decreasing the expression of pivotal inflammatory mediators and inhibiting endothelial apoptosis to preserve the pulmonary barrier function in septic rats.
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22
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Jung CY, Bae JM. Pathophysiology and protective approaches of gut injury in critical illness. Yeungnam Univ J Med 2020; 38:27-33. [PMID: 33022904 PMCID: PMC7787898 DOI: 10.12701/yujm.2020.00703] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022] Open
Abstract
The gut is a complex organ that has played an important role in digestion, absorption, endocrine functions, and immunity. The gut mucosal barriers consist of the immunologic barrier and nonimmunologic barrier. During critical illnesses, the gut is susceptible to injury due to the induction of intestinal hyperpermeability. Gut hyperpermeability and barrier dysfunction may lead to systemic inflammatory response syndrome. Additionally, gut microbiota are altered during critical illnesses. The etiology of such microbiome alterations in critical illnesses is multifactorial. The interaction or systemic host defense modulation between distant organs and the gut microbiome is increasingly studied in disease research. No treatment modality exists to significantly enhance the gut epithelial integrity, permeability, or mucus layer in critically ill patients. However, multiple helpful approaches including clinical and preclinical strategies exist. Enteral nutrition is associated with an increased mucosal barrier in animal and human studies. The trophic effects of enteral nutrition might help to maintain the intestinal physiology, prevent atrophy of gut villi, reduce intestinal permeability, and protect against ischemia-reperfusion injury. The microbiome approach such as the use of probiotics, fecal microbial transplantation, and selective decontamination of the digestive tract has been suggested. However, its evidence does not have a high quality. To promote rapid hypertrophy of the small bowel, various factors have been reported, including the epidermal growth factor, membrane permeant inhibitor of myosin light chain kinase, mucus surrogate, pharmacologic vagus nerve agonist, immune-enhancing diet, and glucagon-like peptide-2 as preclinical strategies. However, the evidence remains unclear.
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Affiliation(s)
- Chang Yeon Jung
- Department of Surgery, Yeungnam University Hospital, Daegu, Korea
| | - Jung Min Bae
- Department of Surgery, Yeungnam University College of Medicine, Daegu, Korea
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23
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Ma Y, Zabell T, Creasy A, Yang X, Chatterjee V, Villalba N, Kistler EB, Wu MH, Yuan SY. Gut Ischemia Reperfusion Injury Induces Lung Inflammation via Mesenteric Lymph-Mediated Neutrophil Activation. Front Immunol 2020; 11:586685. [PMID: 33042165 PMCID: PMC7517702 DOI: 10.3389/fimmu.2020.586685] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 08/21/2020] [Indexed: 12/15/2022] Open
Abstract
Gut ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidities that result from systemic inflammation and remote organ dysfunction, typically acute lung injury. The mechanisms underlying the dissemination of gut-derived harmful mediators into the circulation are poorly understood. The objective of our study was to determine the role of mesenteric lymphatic circulation in the systemic and pulmonary inflammatory response to gut I/R. Using a murine intestinal I/R model, we evaluated whether and how blocking mesenteric lymph flow affects the inflammatory response in local tissues (gut) and remote organs (lungs). We further explored the mechanisms of post-I/R lymph-induced systemic inflammation by examining neutrophil activity and interaction with endothelial cells in vitro. Mice subjected to intestinal I/R displayed a significant inflammatory response in local tissues, evidenced by neutrophil infiltration into mucosal areas, as well as lung inflammation, evidenced by increased myeloperoxidase levels, neutrophil infiltration, and elevated microvascular permeability in the lungs. Mesenteric lymph duct ligation (MLDL) had no effect on gut injury per se, but effectively attenuated lung injury following gut I/R. Cell experiments showed that lymph fluid from post-I/R animals, but not pre-I/R, increased neutrophil surface CD11b expression and their ability to migrate across vascular endothelial monolayers. Moreover, post-I/R lymph upregulated neutrophil expression of pro-inflammatory cytokines and chemokines, which was mediated by a mechanism involving nuclear factor (NF)-κB signaling. Consistently, gut I/R activated NF-κB in lung neutrophils, which was alleviated by MLDL. In conclusion, all these data indicate that mesenteric lymph circulation contributes to neutrophil activation and lung inflammation following gut I/R injury partly through activating NF-κB.
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Affiliation(s)
- Yonggang Ma
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Taylor Zabell
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Alexandra Creasy
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Xiaoyuan Yang
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Victor Chatterjee
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Nuria Villalba
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Erik B. Kistler
- Department of Anesthesiology and Critical Care, University of California, San Diego, Veterans Affairs San Diego Healthcare System, San Diego, CA, United States
| | - Mack H. Wu
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, United States
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
| | - Sarah Y. Yuan
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, United States
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Stakelum A, Zaborowski A, Collins D, Winter DC. The influence of the gastrointestinal microbiome on colorectal metastasis: a narrative review. Colorectal Dis 2020; 22:1101-1107. [PMID: 31869511 DOI: 10.1111/codi.14930] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 11/12/2019] [Indexed: 02/08/2023]
Abstract
INTRODUCTION The gastrointestinal microbiome has been suggested to contribute to the development of both primary and secondary colorectal cancer. Despite advances in understanding the prognostic and predictive value of clinico-pathological parameters, the underlying mechanisms that result in progression to metastatic disease have yet to be defined. The metastatic cascade involves a number of sequential steps, including detachment of tumour cells from the primary site, intravasation and dissemination within the circulatory and lymphatic systems, with extravasation and proliferation at a secondary site. OBJECTIVE An analysis of the literature relating to the gastrointestinal microbiome and its role in colorectal metastasis was conducted. This review aims to examine the current evidence supporting a role for the microbiome in colorectal metastasis and to describe the mechanisms by which it may contribute to metastatic progression. CONCLUSION The invasive pathways utilized by bacteria and how they may be manipulated by tumour cells for migration and metastasis are presented and the potential of the intestinal microbiome as a therapeutic target in colorectal carcinogenesis and metastasis is detailed here.
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Affiliation(s)
- A Stakelum
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland
| | - A Zaborowski
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland
| | - D Collins
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland
| | - D C Winter
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin 4, Ireland
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Ashley SL, Sjoding MW, Popova AP, Cui TX, Hoostal MJ, Schmidt TM, Branton WR, Dieterle MG, Falkowski NR, Baker JM, Hinkle KJ, Konopka KE, Erb-Downward JR, Huffnagle GB, Dickson RP. Lung and gut microbiota are altered by hyperoxia and contribute to oxygen-induced lung injury in mice. Sci Transl Med 2020; 12:eaau9959. [PMID: 32801143 PMCID: PMC7732030 DOI: 10.1126/scitranslmed.aau9959] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 06/14/2019] [Accepted: 01/21/2020] [Indexed: 12/27/2022]
Abstract
Inhaled oxygen, although commonly administered to patients with respiratory disease, causes severe lung injury in animals and is associated with poor clinical outcomes in humans. The relationship between hyperoxia, lung and gut microbiota, and lung injury is unknown. Here, we show that hyperoxia conferred a selective relative growth advantage on oxygen-tolerant respiratory microbial species (e.g., Staphylococcus aureus) as demonstrated by an observational study of critically ill patients receiving mechanical ventilation and experiments using neonatal and adult mouse models. During exposure of mice to hyperoxia, both lung and gut bacterial communities were altered, and these communities contributed to oxygen-induced lung injury. Disruption of lung and gut microbiota preceded lung injury, and variation in microbial communities correlated with variation in lung inflammation. Germ-free mice were protected from oxygen-induced lung injury, and systemic antibiotic treatment selectively modulated the severity of oxygen-induced lung injury in conventionally housed animals. These results suggest that inhaled oxygen may alter lung and gut microbial communities and that these communities could contribute to lung injury.
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Affiliation(s)
- Shanna L Ashley
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Michael W Sjoding
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
- Michigan Center for Integrative Research in Critical Care, Ann Arbor, MI, USA
| | - Antonia P Popova
- Division of Pediatric Pulmonology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Tracy X Cui
- Division of Pediatric Pulmonology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Matthew J Hoostal
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Thomas M Schmidt
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - William R Branton
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Michael G Dieterle
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Nicole R Falkowski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jennifer M Baker
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kevin J Hinkle
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kristine E Konopka
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - John R Erb-Downward
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gary B Huffnagle
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
- Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, MI, USA
| | - Robert P Dickson
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
- Michigan Center for Integrative Research in Critical Care, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
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Abstract
Dysfunction of the gut-blood barrier plays an important role in many diseases, such as inflammatory bowel disease, hemorrhagic shock (HS), or burn injury. However, little is known about gut barrier dysfunction after hemodynamically instable polytrauma (PT). Therefore, we aimed to evaluate the effects of PT and HS on remote intestinal damage and barrier dysfunction, especially regarding the role of zonula occludens protein 1 (ZO-1) as an important tight junction protein.Male C57BL/6 mice were subjected to either PT (thorax trauma, closed head injury, soft tissue injury, and distal femoral fracture), 60 min of pressure-controlled HS (30 ± 5 mmHg), or PT+HS, or sham procedures.Animals of all trauma groups showed an increase in abdominal girth and dilation of the intestine during the experimental period, which was largest in the PT+HS group. Increased blood-tissue permeability to albumin (assessed by Evans blue dye) was found in the HS group. Experimental groups showed a slight increase in plasma concentration of intestinal fatty acid binding protein and some intestinal damage was histologically detectable. Of note, PT+HS animals revealed significantly reduced expression of ZO-1 in intestinal epithelial cells. In an in-vitro model, stimulation of human colon epithelial cells with peptidoglycan, but not with lipopolysaccharide, resulted in elevated secretion of pro-inflammatory cytokines, reflecting inflammatory activity of the intestinal epithelium.Taken together, PT and HS lead to increased permeability of the gut-blood barrier. Bacterial components may lead to production of inflammatory and chemotactic mediators by gut epithelial cells, underlining the role of the gut as an immunologically active organ.
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Williams EC, Coimbra R, Chan TW, Baird A, Eliceiri BP, Costantini TW. Precious cargo: Modulation of the mesenteric lymph exosome payload after hemorrhagic shock. J Trauma Acute Care Surg 2020; 86:52-61. [PMID: 30576304 DOI: 10.1097/ta.0000000000002093] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Trauma/hemorrhagic shock (T/HS) causes a release of proinflammatory mediators into the mesenteric lymph (ML) that may trigger a systemic inflammatory response and subsequent organ failure. Recently, we showed that exosomes in postshock ML are biologically active mediators of this inflammation. Because the specific inflammatory mediators in postshock ML exosomes have yet to be characterized, we hypothesized that T/HS would lead to a distinct ML proinflammatory exosome phenotype that could be identified by proteomic analysis. We further hypothesized that their regulation by the neuroenteric axis via the vagus nerve would modify this proinflammatory profile. METHODS Male rats underwent an established T/HS model including 60 minutes of HS followed by resuscitation. Mesenteric lymph was collected before HS (preshock) and after resuscitation (postshock). A subset of animals underwent cervical vagus nerve electrical stimulation (VNS) after the HS phase. Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) followed by protein identification, label free quantification, and bioinformatic analysis was performed on exosomes from the pre-shock and post-shock phases in the T/HS and T/HS + vagus nerve electrical stimulation groups. Biological activity of exosomes was evaluated using a monocyte nuclear factor kappa B (NF-κB) activity assay. RESULTS ML exosomes express a distinct protein profile after T/HS with enrichment in pathways associated with cell signaling, cell death and survival, and the inflammatory response. Stimulation of the vagus nerve following injury attenuated the transition of ML exosomes to this T/HS-induced inflammatory phenotype with protein expression remaining similar to pre-shock. Monocyte NF-κB activity was increased after exposure to ML exosomes harvested after T/HS, while ML exosomes from preshock had no effect on monocyte NF-κB expression. CONCLUSION Postshock ML exosomes carry a distinct, proinflammatory protein cargo. Stimulating the vagus nerve prevents the T/HS-induced changes in ML exosome protein payload and suggests a novel mechanism by which the neuroenteric axis may limit the systemic inflammatory response after injury.
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Affiliation(s)
- Elliot C Williams
- From the Division of Trauma, Surgical Critical Care, Burns and Acute Care Surgery, Department of Surgery, University of California San Diego Health, San Diego, California (E.C.W., T.W.C., A.B., B.P.E., T.W.C.); and Riverside University Health System Medical Center, Loma Linda University School of Medicine, Moreno Valley, California (R.C.)
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Yagi M, Morishita K, Ueno A, Nakamura H, Akabori H, Senda A, Kojima M, Aiboshi J, Costantini T, Coimbra R, Otomo Y. Electrical stimulation of the vagus nerve improves intestinal blood flow after trauma and hemorrhagic shock. Surgery 2019; 167:638-645. [PMID: 31759624 DOI: 10.1016/j.surg.2019.09.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 09/05/2019] [Accepted: 09/26/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Gut damage after trauma/hemorrhagic shock contributes to multiple organ dysfunction syndrome. Electrical vagal nerve stimulation is known to prevent gut damage in animal models of trauma/hemorrhagic shock by altering the gut inflammatory response; however, the effect of vagal nerve stimulation on intestinal blood flow, which is an essential function of the vagus nerve, is unknown. This study aimed to determine whether vagal nerve stimulation influences the abdominal vagus nerve activity, intestinal blood flow, gut injury, and the levels of autonomic neuropeptides. METHODS Male Sprague Dawley rats were anesthetized, and the cervical and abdominal vagus nerves were exposed. One pair of bipolar electrodes was attached to the cervical vagus nerve to stimulate it; another pair of bipolar electrodes were attached to the abdominal vagus nerve to measure action potentials. The rats underwent trauma/hemorrhagic shock (with maintenance of mean arterial pressure of 25 mmHg for 30 min) without fluid resuscitation and received cervical vagal nerve stimulation post-injury. A separate cohort of animals were subjected to transection of the abdominal vagus nerve (vagotomy) just before the start of cervical vagal nerve stimulation. Intestinal blood flow was measured by laser Doppler flowmetry. Gut injury and noradrenaline level in the portal venous plasma were also assessed. RESULTS Vagal nerve stimulation evoked action potentials in the abdominal vagus nerve and caused a 2-fold increase in intestinal blood flow compared to the shock phase (P < .05). Abdominal vagotomy eliminated the effect of vagal nerve stimulation on intestinal blood flow (P < .05). Vagal nerve stimulation protected against trauma/hemorrhagic shock -induced gut injury (P < .05), and circulating noradrenaline levels were decreased after vagal nerve stimulation (P < .05). CONCLUSION Cervical vagal nerve stimulation evoked abdominal vagal nerve activity and relieved the trauma/hemorrhagic shock-induced impairment in intestinal blood flow by modulating the vasoconstriction effect of noradrenaline, which provides new insight into the protective effect of vagal nerve stimulation.
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Affiliation(s)
- Masayuki Yagi
- Department of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Koji Morishita
- Department of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
| | - Akinori Ueno
- Department of Electrical and Electronic Engineering, School of Engineering, Tokyo Denki University, Tokyo, Japan
| | - Hajime Nakamura
- Department of Electrical and Electronic Engineering, School of Engineering, Tokyo Denki University, Tokyo, Japan
| | - Hiroya Akabori
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Atsushi Senda
- Department of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Mitsuaki Kojima
- Department of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Junichi Aiboshi
- Department of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Todd Costantini
- Division of Trauma, Surgical Critical Care, Burns and Acute Care Surgery, Department of Surgery, University of California, SanDiego, CA
| | - Raul Coimbra
- Riverside University Health System Medical Center and Loma Linda University School of Medicine, Riverside, CA
| | - Yasuhiro Otomo
- Department of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
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Powell K, Shah K, Hao C, Wu YC, John A, Narayan RK, Li C. Neuromodulation as a new avenue for resuscitation in hemorrhagic shock. Bioelectron Med 2019; 5:17. [PMID: 32232106 PMCID: PMC7098257 DOI: 10.1186/s42234-019-0033-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023] Open
Abstract
Hemorrhagic shock (HS), a major cause of early death from trauma, accounts for around 40% of mortality, with 33–56% of these deaths occurring before the patient reaches a medical facility. Intravenous fluid therapy and blood transfusions are the cornerstone of treating HS. However, these options may not be available soon after the injury, resulting in death or a poorer quality of survival. Therefore, new strategies are needed to manage HS patients before they can receive definitive care. Recently, various forms of neuromodulation have been investigated as possible supplementary treatments for HS in the prehospital phase of care. Here, we provide an overview of neuromodulation methods that show promise to treat HS, such as vagus nerve stimulation, electroacupuncture, trigeminal nerve stimulation, and phrenic nerve stimulation and outline their possible mechanisms in the treatment of HS. Although all of these approaches are only validated in the preclinical models of HS and are yet to be translated to clinical settings, they clearly represent a paradigm shift in the way that this deadly condition is managed in the future.
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Affiliation(s)
- Keren Powell
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, NY USA
| | - Kevin Shah
- Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY USA
| | - Caleb Hao
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, NY USA
| | - Yi-Chen Wu
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, NY USA
| | - Aashish John
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, NY USA
| | - Raj K Narayan
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, NY USA
| | - Chunyan Li
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, NY USA.,Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY USA.,Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY 11030 USA
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32
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Mortaz E, Zadian SS, Shahir M, Folkerts G, Garssen J, Mumby S, Adcock IM. Does Neutrophil Phenotype Predict the Survival of Trauma Patients? Front Immunol 2019; 10:2122. [PMID: 31552051 PMCID: PMC6743367 DOI: 10.3389/fimmu.2019.02122] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Accepted: 08/23/2019] [Indexed: 12/14/2022] Open
Abstract
According to the World Health Organization (WHO), trauma is responsible for 10% of deaths and 16% of disabilities worldwide. This is considerably higher than those for malaria, tuberculosis, and HIV/AIDS combined. While the human suffering and death caused by injury is well-recognized, injury has a significant medical care cost. Better prediction of the state of trauma patients in the days immediately after trauma may reduce costs. Traumatic injuries to multiple organs can cause dysfunction in all systems of the body especially the immune system placing patients at high risk of infections and inflammatory complications which are often fatal. Neutrophils are the most abundant leukocyte in the human circulation and are crucial for the prevention of microbial disease. Significant changes in neutrophil functions such as enhanced chemotaxis, Neutrophil extracellular trap (NET)-induced cell death (NETosis), and phagocytosis occur early after injury followed by prolonged functional defects such as phagocytosis, killing mechanisms, and receptor expression. Analysis of these changes may improve the prediction of the patient's condition over time. We provide a comprehensive and up-to-date review of the literature investigating the effect of trauma on neutrophil phenotype with an underlying goal of using this knowledge to examine the predictive potential of neutrophil alterations on secondary complications in patients with traumatic injuries. We conclude that alterations in neutrophil surface markers and functions may be potential biomarkers that predict the outcome of trauma patients.
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Affiliation(s)
- Esmaeil Mortaz
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Sajjad Zadian
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehri Shahir
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gert Folkerts
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.,Nutricia Research Centre for Specialized Nutrition, Utrecht, Netherlands
| | - Sharon Mumby
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Ian M Adcock
- National Heart and Lung Institute, Imperial College London, London, United Kingdom.,Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
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Castillo R, Schander A, Hodge LM. Lymphatic Pump Treatment Mobilizes Bioactive Lymph That Suppresses Macrophage Activity In Vitro. J Osteopath Med 2019; 118:455-461. [PMID: 29946663 DOI: 10.7556/jaoa.2018.099] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Context By promoting the recirculation of tissue fluid, the lymphatic system preserves tissue health, aids in the absorption of gastrointestinal lipids, and supports immune surveillance. Failure of the lymphatic system has been implicated in the pathogenesis of several infectious and inflammatory diseases. Thus, interventions that enhance lymphatic circulation, such as osteopathic lymphatic pump treatment (LPT), should aid in the management of these diseases. Objective To determine whether thoracic duct lymph (TDL) mobilized during LPT would alter the function of macrophages in vitro. Methods The thoracic ducts of 6 mongrel dogs were cannulated, and TDL samples were collected before (baseline), during, and 10 minutes after LPT. Thoracic duct lymph flow was measured, and TDL samples were analyzed for protein concentration. To measure the effect of TDL on macrophage activity, RAW 264.7 macrophages were cultured for 1 hour to acclimate. After 1 hour, cell-free TDL collected at baseline, during LPT, and after TDL was added at 5% total volume per well and co-cultured with or without 500 ng per well of lipopolysaccharide (LPS) for 24 hours. As a control for the addition of 5% TDL, macrophages were cultured with phosphate-buffered saline (PBS) at 5% total volume per well and co-cultured with or without 500 ng per well of LPS for 24 hours. After culture, cell-free supernatants were assayed for nitrite (NO2-), tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10). Macrophage viability was measured using flow cytometry. Results Lymphatic pump treatment significantly increased TDL flow and the flux of protein in TDL (P<.001). After culture, macrophage viability was approximately 90%. During activation with LPS, baseline TDL, TDL during LPT, and TDL after LPT significantly decreased the production of NO2-, TNF-α, and IL-10 by macrophages (P<.05). However, no significant differences were found in viability or the production of NO2-, TNF-α, or IL-10 between macrophages cultured with LPS plus TDL taken before, during, and after LPT (P>.05). Conclusion The redistribution of protective lymph during LPT may provide scientific rationale for the clinical use of LPT to reduce inflammation and manage edema.
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Mai N, Miller-Rhodes K, Knowlden S, Halterman MW. The post-cardiac arrest syndrome: A case for lung-brain coupling and opportunities for neuroprotection. J Cereb Blood Flow Metab 2019; 39:939-958. [PMID: 30866740 PMCID: PMC6547189 DOI: 10.1177/0271678x19835552] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Systemic inflammation and multi-organ failure represent hallmarks of the post-cardiac arrest syndrome (PCAS) and predict severe neurological injury and often fatal outcomes. Current interventions for cardiac arrest focus on the reversal of precipitating cardiac pathologies and the implementation of supportive measures with the goal of limiting damage to at-risk tissue. Despite the widespread use of targeted temperature management, there remain no proven approaches to manage reperfusion injury in the period following the return of spontaneous circulation. Recent evidence has implicated the lung as a moderator of systemic inflammation following remote somatic injury in part through effects on innate immune priming. In this review, we explore concepts related to lung-dependent innate immune priming and its potential role in PCAS. Specifically, we propose and investigate the conceptual model of lung-brain coupling drawing from the broader literature connecting tissue damage and acute lung injury with cerebral reperfusion injury. Subsequently, we consider the role that interventions designed to short-circuit lung-dependent immune priming might play in improving patient outcomes following cardiac arrest and possibly other acute neurological injuries.
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Affiliation(s)
- Nguyen Mai
- 1 Department of Neuroscience, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
| | - Kathleen Miller-Rhodes
- 1 Department of Neuroscience, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
| | - Sara Knowlden
- 2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,3 Department of Neurology, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
| | - Marc W Halterman
- 1 Department of Neuroscience, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,2 Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA.,3 Department of Neurology, School of Medicine and Dentistry, The University of Rochester, Rochester, NY, USA
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35
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Rivera ED, Coffey JC, Walsh D, Ehrenpreis ED. The Mesentery, Systemic Inflammation, and Crohn's Disease. Inflamm Bowel Dis 2019; 25:226-234. [PMID: 29920595 DOI: 10.1093/ibd/izy201] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Indexed: 12/11/2022]
Abstract
Initially thought to be a structure that only provided support to the abdominal contents, the mesentery has now gained special attention in the scientific community. The new approach of studying the mesentery as an individual organ has highlighted its importance in the development of local and systemic inflammatory diseases and its potential role in Crohn's disease. Its topographical relationship with the intestine in the setting of active inflammation and "creeping fat" is possibly one of the most important arguments for including the mesentery as an important factor in the pathogenesis of Crohn's disease. In this review, we discuss the importance of the mesentery from the anatomical and embryological standpoints. We also will summarize data on mesenteric inflammation in patients with Crohn's disease. The significance of the mesentery in systemic inflammatory syndromes will be discussed, and we provide an overview of primary inflammatory disorders of the mesentery. Finally, we discuss surgical approaches for patients requiring resection for Crohn's disease that incorporate mesenteric factors, pointing out recent data suggesting that these have the potential for improving outcomes and reducing disease recurrence. 10.1093/ibd/izy201_video1izy201.video15794169491001.
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Affiliation(s)
- Edgardo D Rivera
- Division of Gastroenterology, Hepatology and Nutrition, University of Miami Miller School of Medicine, Mailman Center for Child Development, Miami, Florida
| | - John Calvin Coffey
- FRCSI Surgery, Graduate Entry Medical School, University of Limerick, Limerick, Ireland.,Department of Surgery, University Hospital Limerick Group, Limerick, Ireland
| | - Dara Walsh
- Department of Surgery, University Hospital Limerick Group, Limerick, Ireland
| | - Eli D Ehrenpreis
- Rosalind Franklin University Medical School, North Chicago, Illinois.,Division of Gastroenterology, Hepatology and Nutrition, University of Miami Miller School of Medicine, Miami, Florida.,Advocate Lutheran General Hospital, Park Ridge, Illinois
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Breslin JW, Yang Y, Scallan JP, Sweat RS, Adderley SP, Murfee WL. Lymphatic Vessel Network Structure and Physiology. Compr Physiol 2018; 9:207-299. [PMID: 30549020 PMCID: PMC6459625 DOI: 10.1002/cphy.c180015] [Citation(s) in RCA: 202] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease. © 2019 American Physiological Society. Compr Physiol 9:207-299, 2019.
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Affiliation(s)
- Jerome W. Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Ying Yang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Joshua P. Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Richard S. Sweat
- Department of Biomedical Engineering, Tulane University, New Orleans, LA
| | - Shaquria P. Adderley
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - W. Lee Murfee
- Department of Biomedical Engineering, University of Florida, Gainesville, FL
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Huang HH, Lee YC, Chen CY. Effects of burns on gut motor and mucosa functions. Neuropeptides 2018; 72:47-57. [PMID: 30269923 DOI: 10.1016/j.npep.2018.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/16/2018] [Accepted: 09/19/2018] [Indexed: 02/08/2023]
Abstract
This review analyzed the published studies on the effects of thermal injury on gastrointestinal motility and mucosal damage. Our strategy was to integrate all available evidence to provide a complete review on the prokinetic properties of variable reagents and the potential clinical treatment of mucosal damage and gastrointestinal dysmotility after thermal injury. We classified the studies into two major groups: studies on gastrointestinal dysmotility and studies on mucosal damage. We also subclassified the studies into 3 parts: stomach, small intestine, and colon. This review shows evidence that ghrelin can recover burn-induced delay in gastric emptying and small intestinal transit, and can protect the gastric mucosa from burn-induced injury. Oxytocin and β-glucan reduced the serum inflammatory mediators, and histological change and mucosal damage indicators, but did not show evidence of having the ability to recover gastrointestinal motility. Using a combination of different reagents to protect the gastrointestinal mucosa against damage and to recover gastrointestinal motility is an alternative treatment for thermal injury.
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Affiliation(s)
- Hsien-Hao Huang
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Yu-Chi Lee
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Yen Chen
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Taiwan Association for the Study of Small Intestinal Diseases, Guishan, Taiwan.
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Gut-origin sepsis in the critically ill patient: pathophysiology and treatment. Infection 2018; 46:751-760. [PMID: 30003491 DOI: 10.1007/s15010-018-1178-5] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 07/06/2018] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Gut permeability is increased in critically ill patients, and associated with the development of the systemic inflammatory response syndrome and multiple organ dysfunction syndrome (MODS). The pathogenetic link(s) and potential therapies are an area of intense research over the last decades. METHODS We thoroughly reviewed the literature on gut-origin sepsis and MODS in critically ill patients, with emphasis on the implicated pathophysiological mechanisms and therapeutic interventions. FINDINGS Intestinal barrier failure leading to systemic bacterial translocation associated with MODS was the predominant pathophysiological theory for several years. However, clinical studies with critically ill patients failed to provide the evidence of systemic spread of gut-derived bacteria and/or their products as a cause of MODS. Newer experimental data highlight the role of the mesenteric lymph as a carrier of gut-derived danger-associated molecular patterns (DAMPs) to the lung and the systemic circulation. These substances are recognized by pattern recognition receptor-bearing cells in diverse tissues and promote proinflammatory pathways and the development MODS. Therefore, the gut becomes a pivotal proinflammatory organ, driving the systemic inflammatory response through DAMPs release in mesenteric lymph, without the need for systemic bacterial translocation. CONCLUSIONS There is an emerging need for application of sensitive non-invasive and easily measured biomarkers of early intestinal injury (e.g., citrulline, intestinal fatty acid protein, and zonulin) in our everyday clinical practice, guiding the early pharmacological intervention in critically ill patients to restore or prevent intestinal injury and improve their outcomes.
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Abstract
PURPOSE OF REVIEW The review aims to discuss emerging evidence in the field of microbiome-dependent roles in host defense during critical illness with a focus on lung, kidney, and brain inflammation. RECENT FINDINGS The gut microbiota of critical ill patients is characterized by lower diversity, lower abundances of key commensal genera, and in some cases overgrowth by one bacterial genera, a state otherwise known as dysbiosis. Increasing evidence suggests that microbiota-derived components can reach the circulatory system from the gut and modulate immune homeostasis. Dysbiosis might have greater consequences for the critically ill than previously imagined and could contribute to poor outcome. Preclinical studies suggest that impaired communication across the gut - organ axes is associated with brain, lung - and kidney failure. SUMMARY In health, a diverse microbiome might enhance host defense, while during critical illness, the dysbiotic microbiome might contribute to comorbidity and organ dysfunction. Future research should be aimed at further establishing the causes and consequences of dysbiosis seen in the critically ill, which will provide perspective for developing new strategies of intervention.
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Nunns GR, Stringham JR, Gamboni F, Moore EE, Fragoso M, Stettler GR, Silliman CC, Banerjee A. Trauma and hemorrhagic shock activate molecular association of 5-lipoxygenase and 5-lipoxygenase-Activating protein in lung tissue. J Surg Res 2018; 229:262-270. [PMID: 29936999 DOI: 10.1016/j.jss.2018.03.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 02/02/2018] [Accepted: 03/14/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Post-traumatic lung injury following trauma and hemorrhagic shock (T/HS) is associated with significant morbidity. Leukotriene-induced inflammation has been implicated in the development of post-traumatic lung injury through a mechanism that is only partially understood. Postshock mesenteric lymph returning to the systemic circulation is rich in arachidonic acid, the substrate of 5-lipoxygenase (ALOX5). ALOX5 is the rate-limiting enzyme in leukotriene synthesis and, following T/HS, contributes to the development of lung dysfunction. ALOX5 colocalizes with its cofactor, 5-lipoxygenase-activating protein (ALOX5AP), which is thought to potentiate ALOX5 synthetic activity. We hypothesized that T/HS results in the molecular association and nuclear colocalization of ALOX5 and ALOX5AP, which ultimately increases leukotriene production and potentiates lung injury. MATERIALS AND METHODS To examine these molecular interactions, a rat T/HS model was used. Post-T/HS tissue was evaluated for lung injury through both histologic analysis of lung sections and biochemical analysis of bronchoalveolar lavage fluid. Lung tissue was immunostained for ALOX5 and ALOX5AP with association and colocalization evaluated by fluorescence resonance energy transfer. In addition, rats undergoing T/HS were treated with MK-886, a known ALOX5AP inhibitor. RESULTS ALOX5 levels increase and ALOX5/ALOX5AP association occurred after T/HS, as evidenced by increases in total tissue fluorescence and fluorescence resonance energy transfer signal intensity, respectively. These findings coincided with increased leukotriene production and with the histological changes characteristic of lung injury. ALOX5/ALOX5AP complex formation, leukotriene production, and lung injury were decreased after inhibition of ALOX5AP with MK-886. CONCLUSIONS These results suggest that the association of ALOX5/ALOX5AP contributes to leukotriene-induced inflammation and predisposes the T/HS animal to lung injury.
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Affiliation(s)
- Geoffrey R Nunns
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado.
| | - John R Stringham
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado
| | - Fabia Gamboni
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado
| | - Ernest E Moore
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado; Denver Health Medical Center, Department of Surgery, Denver, Colorado
| | - Miguel Fragoso
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado; Denver Health Medical Center, Department of Surgery, Denver, Colorado
| | - Gregory R Stettler
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado
| | - Christopher C Silliman
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado; School of Medicine, Department of Pediatrics-Hematology/Oncology, Children's Hospital Colorado, University of Colorado Denver, Aurora, Colorado; Research Laboratory, Bonfils Blood Center, Denver, Colorado
| | - Anirban Banerjee
- School of Medicine, Department of Surgery, Trauma Research Center, University of Colorado Denver, Aurora, Colorado
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Wang Y, Pati S, Schreiber M. Cellular therapies and stem cell applications in trauma. Am J Surg 2018; 215:963-972. [PMID: 29502858 DOI: 10.1016/j.amjsurg.2018.02.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 02/02/2018] [Accepted: 02/02/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND As the leading cause of mortality in the United States, trauma management have improved drastically over the past few decades with improved resuscitation and hemorrhage control. Stem cells are being used in an attempt to augment healing from trauma. DATA SOURCES PubMed and ClinicalTrials.gov were searched for published and registered pre-clinical and clinical trials for the application of stem cells to AKI, ARDS, shock, infection, TBI, wound healing, and bone healing. CONCLUSIONS Stem cell therapy for augmentation of healing traumatic injuries appears safe, as demonstrated by completed phase I/II trials. Further large scale studies are needed to assess the clinical efficacy.
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Affiliation(s)
- Yuxuan Wang
- Oregon Health and Science University, Department of Trauma, Surgical Critical Care, and Acute Care Surgery, USA.
| | - Shibani Pati
- University of California, San Francisco, Department of Laboratory Medicine, USA
| | - Martin Schreiber
- Oregon Health and Science University, Department of Trauma, Surgical Critical Care, and Acute Care Surgery, USA
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Nakagaki BN, Vieira AT, Rezende RM, David BA, Menezes GB. Tissue macrophages as mediators of a healthy relationship with gut commensal microbiota. Cell Immunol 2018; 330:16-26. [PMID: 29422270 DOI: 10.1016/j.cellimm.2018.01.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 01/26/2018] [Accepted: 01/31/2018] [Indexed: 12/12/2022]
Abstract
Mammals and microorganisms have evolved a complex and tightly controlled mutual relationship. This interaction grants protection and energy source for the microorganisms, and on the other hand, provides several immunologic, metabolic and physiological advantages for the host. The gastrointestinal tract (GI) harbors the largest bacteria diversity within the body and complex mechanisms control microbiota community under homeostasis. However, once disrupted, microbiota imbalance can lead to overt growth of resident and invasive populations, with potential risk for lethal diseases. In these cases, bacteria might also escape from the intestines and reach different organs through the blood and lymphatic circulation. To control these unwanted conditions, all body tissues are populated with resident macrophages that have the ability to capture and eliminate pathogens, avoiding their dissemination. Here we discuss the different routes for bacterial translocation from the intestinal tract, and how macrophages act in the removal of these microorganisms to prevent systemic infections and restore the homeostasis.
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Affiliation(s)
- Brenda Naemi Nakagaki
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil
| | - Angélica Thomaz Vieira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil
| | - Rafael Machado Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Bruna Araujo David
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary. Calgary, Alberta, Canada.
| | - Gustavo Batista Menezes
- Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Brazil.
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β-Blockade use for Traumatic Injuries and Immunomodulation: A Review of Proposed Mechanisms and Clinical Evidence. Shock 2018; 46:341-51. [PMID: 27172161 DOI: 10.1097/shk.0000000000000636] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sympathetic nervous system activation and catecholamine release are important events following injury and infection. The nature and timing of different pathophysiologic insults have significant effects on adrenergic pathways, inflammatory mediators, and the host response. Beta adrenergic receptor blockers (β-blockers) are commonly used for treatment of cardiovascular disease, and recent data suggests that the metabolic and immunomodulatory effects of β-blockers can expand their use. β-blocker therapy can reduce sympathetic activation and hypermetabolism as well as modify glucose homeostasis and cytokine expression. It is the purpose of this review to examine either the biologic basis for proposed mechanisms or to describe current available clinical evidence for the use of β-blockers in traumatic brain injury, spinal cord injury, hemorrhagic shock, acute traumatic coagulopathy, erythropoietic dysfunction, metabolic dysfunction, pulmonary dysfunction, burns, immunomodulation, and sepsis.
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Carr ZJ, Van De Louw A, Fehr G, Li JD, Kunselman A, Ruiz-Velasco V. Increased whole blood FFA2/GPR43 receptor expression is associated with increased 30-day survival in patients with sepsis. BMC Res Notes 2018; 11:41. [PMID: 29338778 PMCID: PMC5771199 DOI: 10.1186/s13104-018-3165-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 01/12/2018] [Indexed: 12/18/2022] Open
Abstract
Objective Sepsis is a condition associated with a dysregulated inflammatory response to infection with significant morbidity. Recent advances have elucidated the vital role that the short chain fatty acid glycoprotein receptor 43 (FFA2/GPR43) plays in inflammatory and immunomodulatory pathways. We hypothesized that elevated whole blood GPR43 RNA expression would be associated with increased 30-day survival in patients admitted with sepsis. Patients (n = 93) admitted to the intensive care unit with the diagnosis of sepsis underwent quantitative real time PCR within 48 h of intensive care unit admission. Clinical and demographical parameters were retrospectively extracted from the chart and compared to quantitative measurements of GPR43 RNA expression. Results Utilizing logistic regression, we found that the odds of mortality decreased for every one-unit increase in GPR43 RNA expression for patients that survived to 30 days [OR = 0.71; 95% CI (0.50, 0.99) p = 0.049]. Using linear regression, we determined that the increase in whole blood GPR43 expression was not associated with whole blood white cell count [r = 0.04; 95% CI (−0.16, 0.24); p = 0.70] or body mass index [r = − 0.07; 95% CI (− 0.23, 0.18); p = 0.81]. We conclude that the GPR43 receptor plays an integral role in survival during and after sepsis.
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Affiliation(s)
- Zyad J Carr
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA.
| | - Andry Van De Louw
- Division of Pulmonary & Critical Care Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA
| | - Graham Fehr
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA
| | - Jialiu D Li
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA
| | - Allen Kunselman
- Department of Public Health Sciences, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA
| | - Victor Ruiz-Velasco
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA
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Chen Z, Zhang Y, Ma L, Ni Y, Zhao H. Nrf2 plays a pivotal role in protection against burn trauma-induced intestinal injury and death. Oncotarget 2017; 7:19272-83. [PMID: 27009867 PMCID: PMC4991382 DOI: 10.18632/oncotarget.8189] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 03/05/2016] [Indexed: 12/30/2022] Open
Abstract
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a basic leucine zipper transcription factor that principally defends against oxidative stress and also plays a unique role in severe sepsis. However, its contribution to intestinal injury and death after burn trauma is unclear.In this study, wild-type (Nrf2+/+) and Nrf2-deficient (Nrf2-/-) mice were subjected to 15% or 30% total body surface area burn or sham injury. Survival, systemic inflammation, and gut injury were determined.Nrf2-/- mice were more susceptible to burn-induced intestinal injury, as characterized by increases in damage to the gut structure and in intestinal permeability. This exacerbation was associated with an increase in the intestinal mRNA expression of inflammatory cytokines (interleukin [IL]-6, IL-1B, monocyte chemotactic protein 1, intercellular adhesion molecule, and vascular cell adhesion molecule) and a decrease in the intestinal mRNA expression of Nrf2-regulated genes (NAD(P)H dehydrogenasequinine-1 and glutamate-cysteine ligase modifier subunit). Nrf2-deficient mice also showed a lower survival rate and higher levels of systemic cytokines (IL-6 and IL-1B) and high-mobility group protein B1 than wild-type mice. This study demonstrates for the first time that mice that lack Nrf2 are more susceptible to burn-induced intestinal injury and have more systemic inflammation and a lower survival rate.
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Affiliation(s)
- Zhao Chen
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yiran Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liang Ma
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yiming Ni
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Haige Zhao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Evaluation of gut-blood barrier dysfunction in various models of trauma, hemorrhagic shock, and burn injury. J Trauma Acute Care Surg 2017; 83:944-953. [DOI: 10.1097/ta.0000000000001654] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Windsor JA, Escott A, Brown L, Phillips AR. Novel strategies for the treatment of acute pancreatitis based on the determinants of severity. J Gastroenterol Hepatol 2017; 32:1796-1803. [PMID: 28294403 DOI: 10.1111/jgh.13784] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 03/04/2017] [Accepted: 03/05/2017] [Indexed: 02/06/2023]
Abstract
Acute pancreatitis (AP) is a common disease for which a specific treatment remains elusive. The key determinants of the outcome from AP are persistent organ failure and infected pancreatic necrosis. The prevention and treatment of these determinants provides a framework for the development of specific treatment strategies. The gut-lymph concept provides a common mechanism for systemic inflammation and organ dysfunction. Acute and critical illness, including AP, is associated with intestinal ischemia and drastic changes in the composition of gut lymph, which bypasses the liver to drain into the systemic circulation immediately proximal to the major organ systems which fail. The external diversion of gut lymph and the targeting of treatments to counter the toxic elements in gut lymph offers novel approaches to the prevention and treatment of persistent organ failure. Infected pancreatic necrosis is increasingly treated with less invasive techniques, the mainstay of which is drainage, both endoscopic and percutaneous. Further improvements will occur with the strategies to accelerate liquefaction and through a fundamental re-design of drains, both of which will increase drainage efficacy. The determinants of severity and outcome in patients admitted with AP provide the basis for innovative treatment strategies. The priorities are to translate the gut-lymph concept to clinical practice and to improve the design and active use of drains for infected complications of AP.
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Affiliation(s)
- John A Windsor
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Alistair Escott
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Lisa Brown
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Anthony Rj Phillips
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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C-peptide attenuates acute lung inflammation in a murine model of hemorrhagic shock and resuscitation by reducing gut injury. J Trauma Acute Care Surg 2017; 83:256-262. [PMID: 28452895 DOI: 10.1097/ta.0000000000001539] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The study aims to evaluate whether C-peptide can reduce gut injury during hemorrhagic shock (HS) and resuscitation (R) therefore attenuate shock-induced inflammation and subsequent acute lung injury. METHODS Twelve-week-old male mice (C57/BL6) were hemorrhaged (mean arterial blood pressure maintained at 35 mm Hg for 60 minutes) and then resuscitated with Ringer's lactate, followed by red blood cell transfusion with (HS/R) or without C-peptide (HS/R + C-peptide). Mouse gut permeability, bacterial translocation into the circulatory system and intestinal pathology, circulating HMGB1, and acute lung injury were assessed at different times after R. The mice in the control group underwent sham procedures without HS. RESULTS Compared to the sham group, the mice in the HS/R group showed increased gut permeability (6.07 ± 3.41 μg of FD4/mL) and bacterial translocation into the circulatory system (10.05 ± 4.92, lipopolysaccharide [LPS] of pg/mL), and increased gut damage; conversely, mice in the HS/R + C-peptide group showed significantly reduced gut permeability (1.59 ± 1.39 μg of FD4/mL; p < 0.05) and bacterial translocation (4.53 ± 1.08 pg of LPS/mL; p < 0.05) with reduced intestine damage. In addition, mice in the HS/R group had increased circulating HMGB1 (21.64 ± 14.17 ng/mL), lung myeloperoxidase) activity (34.4 ± 8.91 mU/g of tissue), and pulmonary protein leakage (2.33 ± 1.16 μg Evans blue/g tissue per minute). Mice in the HS/R + C-peptide group showed decreased HMGB1 (7.27 ± 1.93 ng/mL; p < 0.05), lung myeloperoxidase (23.73 ± 8.39 mU/g of tissue; p < 0.05), and pulmonary protein leakage (1.17 ± 0.42 Evans Blue/g tissue per minute; p < 0.05). CONCLUSION Our results indicate that C-peptide exerts beneficial effects to attenuate gut injury and dysfunction, therefore diminishing lung inflammation and subsequent injury in mice with HS and R.
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Exosomes, not protein or lipids, in mesenteric lymph activate inflammation: Unlocking the mystery of post-shock multiple organ failure. J Trauma Acute Care Surg 2017; 82:42-50. [PMID: 27779585 DOI: 10.1097/ta.0000000000001296] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Previous studies have shown that mesenteric lymph (ML) has a crucial role in driving the systemic inflammatory response after trauma/hemorrhagic shock (T/HS). The specific mediators in the ML that contribute to its biological activity remain unclear despite decades of study. Exosomes are extracellular vesicles that are shed into body fluids such as serum and urine that can mediate intercellular communication. We hypothesized that exosomes are present in the ML after trauma/shock and are responsible for the biological activity of ML. METHODS Male rats underwent cannulation of the vessels and mesenteric lymph duct. T/HS was induced by laparotomy and 60 minutes of HS (mean arterial pressure, 35 mmHg), followed by resuscitation. The ML was collected during three distinct time periods (pre-shock, shock, and resuscitation phase) and subsequently separated into exosome and supernatant fractions. Exosomes were characterized by electron microscope, nanoparticle tracking analysis, and immunoblotting. The biological activity of exosomes and supernatant of ML were characterized using a monocyte NF-κB reporter assay and by measuring macrophage intracellular TNF-α production. RESULTS Exosomes were identified in ML by size and expression of the exosome markers CD63 and HSP70. The number of exosomes present in the ML was 2-fold increased during shock and 4-fold decreased in resuscitation phase compared to pre-shock. However, biological activity of exosomes isolated during the resuscitation phase was markedly increased and caused an 8-fold increase in monocyte NF-κB activation compared to supernatant. Macrophage TNF-α production was also increased after exposure to exosomes harvested in the resuscitation phase. The ML supernatant fraction had no effect on TNF-α production during any phase. CONCLUSIONS Our findings show that exosomes, and not the liquid fraction of ML, are the major component triggering inflammatory responses in monocytes and macrophages after experimental T/HS.
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Sun HD, Liu YJ, Chen J, Chen MY, Ouyang B, Guan XD. The pivotal role of HIF-1α in lung inflammatory injury induced by septic mesenteric lymph. Biomed Pharmacother 2017; 91:476-484. [DOI: 10.1016/j.biopha.2017.04.103] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 04/13/2017] [Accepted: 04/23/2017] [Indexed: 11/16/2022] Open
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