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Schnabel C, Harnisch LO, Walter D, Blaurock-Möller N, Bauer M, Quintel M, Kiehntopf M. Association of the C-terminal 42-peptide fragment of alpha-1 antitrypsin with the severity of ARDS: A pilot study. Clin Biochem 2023; 111:41-46. [PMID: 36244468 DOI: 10.1016/j.clinbiochem.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/01/2022] [Accepted: 10/10/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Acute respiratory distress syndrome is a life-threatening condition with a hospital mortality rate of up to 40%. Biomarkers related to the pathophysiology of ARDS may not only identify patients at risk but may also serve as potential therapeutic targets. This study examined the association between the proteolytic C-terminal 42-peptide fragment of alpha-1 antitrypsin and ARDS severity. METHODS The 42-peptide fragment and interleukin-6 levels were measured in 21 patients with mild-to-moderate ARDS and 47 patients with moderate-to-severe ARDS on days 1, 3, and 5 after diagnosis/admission to the intensive care unit. To elucidate the association between both biomarkers and the PaO2/FiO2 ratio, the concentrations of both biomarkers were compared between the two groups, and a multivariate regression analysis was performed. RESULTS The concentrations of both biomarkers were higher in patients with moderate-to-severe ARDS. While the PaO2/FiO2 ratio increased from day 1 to day 3, the concentrations of both biomarkers decreased. Multivariate regression analysis revealed negative associations between the PaO2/FiO2 ratio and both the C-terminal 42-peptide of alpha-1 antitrypsin and interleukin-6 on day 1 (beta: -0.138, p = 0.052; beta: -0.096, p = 0.004) and on day 3 (beta: -0.157, p = 0.045; beta: -0.106, p = 0.043). INTERPRETATION The C-terminal 42-peptide of alpha-1 antitrypsin is a new biomarker associated with ARDS severity. Its predictive value in identifying patients at risk of developing moderate-to-severe ARDS must be investigated in additional, independent prospective studies.
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Affiliation(s)
- Claudia Schnabel
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Am Klinikum 1, Jena 07747, Germany; Laboratory Dr. Fenner and Collegues, Bergstrasse 14, Hamburg 20095, Germany; Semmelweis University, Asklepios Medical School Hamburg, Lohmühlenstrasse 1, Hamburg 20099, Germany.
| | - Lars-Olav Harnisch
- Department of Anesthesiology, University of Göttingen Medical School, Robert-Koch-Strasse 40, Göttingen 37075, Germany.
| | - Dominic Walter
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Am Klinikum 1, Jena 07747, Germany.
| | - Nancy Blaurock-Möller
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Am Klinikum 1, Jena 07747, Germany.
| | - Michael Bauer
- Department of Anesthesiology, Jena University Hospital, Am Klinikum 1, Jena 07747, Germany.
| | - Michael Quintel
- Department of Anesthesiology, University of Göttingen Medical School, Robert-Koch-Strasse 40, Göttingen 37075, Germany.
| | - Michael Kiehntopf
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Am Klinikum 1, Jena 07747, Germany.
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Wu J, Zhao X, Xiao C, Xiong G, Ye X, Li L, Fang Y, Chen H, Yang W, Du X. The role of lung macrophages in chronic obstructive pulmonary disease. Respir Med 2022; 205:107035. [PMID: 36343504 DOI: 10.1016/j.rmed.2022.107035] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/17/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) as a common, preventable and treatable chronic respiratory disease in clinic, gets continuous deterioration and we can't take effective intervention at present. Lung macrophages (LMs) are closely related to the occurrence and development of COPD, but the specific mechanism is not completely clear. In this review we will focus on the role of LMs and potential avenues for therapeutic targeting for LMs in COPD.
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Affiliation(s)
- Jianli Wu
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Xia Zhao
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Chuang Xiao
- School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, China
| | - Guosheng Xiong
- Thoracic Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Xiulin Ye
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Lin Li
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Yan Fang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Hong Chen
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Weimin Yang
- School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, China.
| | - Xiaohua Du
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
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Matsui M, Makimoto A, Nishio N, Takahashi Y, Urashima M, Yuza Y. Predictive factors of acute respiratory events during initial induction chemotherapy in patients with advanced neuroblastoma. Cancer Rep (Hoboken) 2022; 5:e1499. [PMID: 34255936 PMCID: PMC9124507 DOI: 10.1002/cnr2.1499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Acute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma. AIMS The present study aimed to identify the predictive factors of ARE, defined as severe hypoxia, during initial induction chemotherapy in patients with newly diagnosed advanced neuroblastoma. METHODS AND RESULTS The medical records of 75 consecutive patients in whom stage III or IV neuroblastoma was newly diagnosed between January 2003 and December 2018 at two medical institutions were retrospectively reviewed. The outcome was ARE, which were assessed by measuring oxygen saturation between days 1 and 14 of initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) or decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mmHg). Possible predictive factors on admission were first screened for using univariate analyses with P = .05, then models of the predictive power of the outcome were evaluated by generating receiver operating characteristic (ROC) curves. Eleven patients (14.7%) had the outcome, including three (4.0%) who required respiratory support in the intensive care unit. The area under the curve of the ROC for the predictive factors screened by univariate analyses was 0.84 (95% confidence interval [CI]: 0.73-0.95) for lactate dehydrogenase (LDH) and 0.90 (95% CI: 0.82-0.98) for the disseminated intravascular coagulation (DIC) score. CONCLUSION The LDH value and DIC score on admission may be clinically useful predictors of ARE during initial induction chemotherapy in patients with advanced neuroblastoma.
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Affiliation(s)
- Motohiro Matsui
- Department of Hematology/OncologyTokyo Metropolitan Children's Medical CenterTokyoJapan
- Division of Molecular EpidemiologyJikei University School of MedicineTokyoJapan
| | - Atsushi Makimoto
- Department of Hematology/OncologyTokyo Metropolitan Children's Medical CenterTokyoJapan
| | - Nobuhiro Nishio
- Department of PediatricsNagoya University Graduate School of MedicineNagoyaJapan
| | - Yoshiyuki Takahashi
- Department of PediatricsNagoya University Graduate School of MedicineNagoyaJapan
| | - Mitsuyoshi Urashima
- Division of Molecular EpidemiologyJikei University School of MedicineTokyoJapan
| | - Yuki Yuza
- Department of Hematology/OncologyTokyo Metropolitan Children's Medical CenterTokyoJapan
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Cesta MC, Zippoli M, Marsiglia C, Gavioli EM, Mantelli F, Allegretti M, Balk RA. The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome. Front Pharmacol 2022; 12:808797. [PMID: 35095519 PMCID: PMC8790527 DOI: 10.3389/fphar.2021.808797] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of Coronavirus Disease 2019 (COVID-19) and an increase in complications including Acute Respiratory Distress Syndrome (ARDS). Due to the lack of therapeutic options for Acute Respiratory Distress Syndrome, recent attention has focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help define effective therapeutic strategies. Interleukin 8 (IL-8) is a pro-inflammatory cytokine that has a role in neutrophil activation and has been identified within the pathogenesis and progression of this disease. The aim of this review is to highlight the role of IL-8 as a biomarker and prognostic factor in modulating the hyperinflammatory response in ARDS. The crucial role of IL-8 in lung inflammation and disease pathogenesis might suggest IL-8 as a possible new therapeutic target to efficiently modulate the hyperinflammatory response in ARDS.
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Affiliation(s)
| | - Mara Zippoli
- Dompé Farmaceutici SpA, Via Tommaso De Amicis, Napoli, Italy
| | | | | | | | | | - Robert A Balk
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Rush Medical College and Rush University Medical Center, Chicago, IL, United States
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Liu XQ, Xue S, Xu JB, Ge H, Mao Q, Xu XH, Jiang HD. Clinical characteristics and related risk factors of disease severity in 101 COVID-19 patients hospitalized in Wuhan, China. Acta Pharmacol Sin 2022; 43:64-75. [PMID: 33742107 PMCID: PMC7976686 DOI: 10.1038/s41401-021-00627-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 02/10/2021] [Indexed: 01/08/2023]
Abstract
Coronavirus disease 2019 (COVID-19) broke out in December 2019. Due its high morbility and mortality, it is necessary to summarize the clinical characteristics of COVID-19 patients to provide more theoretical basis for future treatment. In the current study, we conducted a retrospective analysis of the clinical characteristics of COVID-19 patients and explored the risk factors for the severity of illness. A total of 101 COVID-19 patients hospitalized in Leishenshan Hospital (Wuhan, China) was classified into three sub-types: moderate (n = 47), severe (n = 36), and critical (n = 18); their clinical data were collected from the Electronic Medical Record. We showed that among the 101 COVID-19 patients, the median age was 62 years (IQR 51-74); 50 (49.5%) patients were accompanied by hypertension, while 25 (24.8%) and 22 (21.8%) patients suffered from diabetes and heart diseases, respectively, with complications. All patients were from Wuhan who had a definite history of exposure to the epidemic area. Multivariate logistic regression analysis revealed that older age, diabetes, chronic liver disease, percentage of neutrophils (N%) > 75%, CRP > 4 mg/L, D-dimer > 0.55 mg/L, IL-2R > 710 U/mL, IL-8 > 62 pg/mL, and IL-10 > 9.1 pg/mL were independent variables associated with severe COVID-19. In conclusion, we have identified the independent risk factors for the severity of COVID-19 pneumonia, including older age, diabetes, chronic liver disease, higher levels of N%, CRP, D-dimer, IL-2R, IL-8, and IL-10, providing evidence for more accurate risk prediction.
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Liu Z, Liu D, Wang Z, Zou Y, Wang H, Li X, Zheng D, Zhou G. Association between inflammatory biomarkers and acute respiratory distress syndrome or acute lung injury risk : A systematic review and meta-analysis. Wien Klin Wochenschr 2021; 134:24-38. [PMID: 34860273 PMCID: PMC8813738 DOI: 10.1007/s00508-021-01971-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 10/16/2021] [Indexed: 11/29/2022]
Abstract
Background The relationship between acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) and levels of certain inflammatory factors remains controversial. The purpose of this meta-analysis was to summarize the available studies evaluating the association between levels of inflammatory factors and ARDS/ALI incidence. Methods We searched the PubMed, EmBase, and Cochrane databases for studies published up to July 2017. For each inflammatory factor, a random effects model was employed to pool results from different studies. Results We identified 63 studies that included 6243 patients in our meta-analysis. Overall, the results indicated that the levels of angiopoietin (ANG)-2 (standard mean difference, SMD: 1.34; P < 0.001), interleukin (IL)-1β (SMD: 0.92; P = 0.012), IL‑6 (SMD: 0.66; P = 0.005), and tumor necrosis factor (TNF)-α (SMD: 0.98; P = 0.001) were significantly higher in patients with ARDS/ALI than in unaffected individuals. No significant differences were observed between patients with ARDS/ALI and unaffected individuals in terms of the levels of IL‑8 (SMD: 0.61; P = 0.159), IL-10 (SMD: 1.10; P = 0.231), and plasminogen activator inhibitor (PAI)-1 (SMD: 0.70; P = 0.060). Conclusions ARDS/ALI is associated with a significantly elevated levels of ANG‑2, IL-1β, IL‑6, and TNF‑α, but not with IL‑8, IL-10, and PAI‑1 levels. Supplementary Information The online version of this article (10.1007/s00508-021-01971-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zhenfeng Liu
- Department of Respiratory Medicine, Zunyi Honghuagang District People's Hospital, 185 Wanli Road, HongHuagang District, 563000, Guizhou, China.,Department of Respiratory Medicine, the Third Affiliated Hospital of Zunyi Medical University, 98 Fenghuang Road, Huichuan District, 563000, Guizhou, China
| | - Daishun Liu
- Department of Respiratory Medicine, the Third Affiliated Hospital of Zunyi Medical University, 98 Fenghuang Road, Huichuan District, 563000, Guizhou, China
| | - Zhihua Wang
- Department of Respiratory Medicine, Teaching Hospital of Zunyi Medical College, 134 LinJiapo Road, HongHuagang District, 563000, Guizhou, China
| | - Yugang Zou
- Department of Respiratory Medicine, the Third Affiliated Hospital of Zunyi Medical University, 98 Fenghuang Road, Huichuan District, 563000, Guizhou, China
| | - Haixia Wang
- Department of Respiratory Medicine, Suzhou Science & Technology Town Hospital, 215153, Jiangsu, China
| | - Xiao Li
- Department of Respiratory Medicine, Teaching Hospital of Zunyi Medical College, 134 LinJiapo Road, HongHuagang District, 563000, Guizhou, China
| | - Deliang Zheng
- Department of Respiratory Medicine, Teaching Hospital of Zunyi Medical College, 134 LinJiapo Road, HongHuagang District, 563000, Guizhou, China
| | - Guoqi Zhou
- Department of Respiratory Medicine, Teaching Hospital of Zunyi Medical College, 134 LinJiapo Road, HongHuagang District, 563000, Guizhou, China.
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Sekiya Y, Shimada K, Takahashi H, Kuga C, Komachi S, Miwa K, Kotani T. Evaluation of a simultaneous adsorption device for cytokines and platelet-neutrophil complexes in vitro and in a rabbit acute lung injury model. Intensive Care Med Exp 2021; 9:49. [PMID: 34568985 PMCID: PMC8473513 DOI: 10.1186/s40635-021-00414-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/29/2021] [Indexed: 11/21/2022] Open
Abstract
Background Platelet–neutrophil complexes (PNCs) readily migrate into tissues and induce tissue damage via cytokine or other pathogenic factors release. These actions are involved in onset and progression of acute respiratory distress syndrome (ARDS). Thus, simultaneous removal of cytokines and activated neutrophils, including PNCs by blood purification may prevent development of ARDS and enhance drug effects. The goal of this study was to examine the effect of a newly developed adsorption column (NOA-001) that eliminates cytokines and activated neutrophils in a lung injury model. Results Adsorption of cytokines, such as IL-8, IL-6 and HMGB-1, and PNCs was first measured in vitro. Lung injury was induced by HCl and lipopolysaccharide intratracheal infusion in rabbits ventilated at a low tidal volume (7–8 mL/kg) and PEEP (2.5 cmH2O) for lung protection. Arterial blood gas, hematologic values, plasma IL-8, blood pressure and heart rate were measured, and lung damage was evaluated histopathologically in animals treated with 8-h direct hemoperfusion with or without use of NOA-001. The in vitro adsorption rates for IL-8, IL-6, HMGB-1, activated granulocytes and PNCs were 99.5 (99.4–99.5)%, 63.9 (63.4–63.9)%, 57.6 (57.4–62.1)%, 9.9 (-4.4–21.3)% and 60.9 (49.0–67.6)%, respectively. Absorption of PNCs onto fibers was confirmed microscopically. These adsorption effects were associated with several improvements in the rabbit model. In respiratory function, the PaO2/FIO2 ratios at 8 h were 314 ± 55 mmHg in the NOA-001 group and 134 ± 41 mmHg in the sham group. The oxygenation index and PaCO2 at 8 h were 9.6 ± 3.1 and 57.0 ± 9.6 mmHg in the sham group and 3.0 ± 0.8 and 40.4 ± 4.5 mmHg in the NOA-001 group, respectively (p < 0.05). Blood pH at 8 h reached 7.18 ± 0.06 in the sham group, but was maintained at 7.36 ± 0.03 (within the normal range) in the NOA-001 group (p < 0.05). In lung histopathology, fewer hyaline membrane and inflammatory cells were observed in the NOA-001 group. Conclusion A column for simultaneous removal of cytokines and PNCs showed efficacy for improvement of pulmonary function in an animal model. This column may be effective in support of treatment of ARDS. Supplementary Information The online version contains supplementary material available at 10.1186/s40635-021-00414-7.
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Affiliation(s)
- Yumiko Sekiya
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan.
| | - Kaoru Shimada
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Hiroshi Takahashi
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Chisa Kuga
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Shunsuke Komachi
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Keishi Miwa
- Medical Devices & Materials Research Lab., Advanced Materials Research Labs., Toray Industries, Inc., Shiga, Japan
| | - Toru Kotani
- Department of Intensive Care Medicine, Showa University School of Medicine, Tokyo, Japan
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Giannini HM, Meyer NJ. Genetics of Acute Respiratory Distress Syndrome: Pathways to Precision. Crit Care Clin 2021; 37:817-834. [PMID: 34548135 DOI: 10.1016/j.ccc.2021.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Clinical risk factors alone fail to fully explain acute respiratory distress syndrome (ARDS) risk or ARDS death, suggesting that individual risk factors contribute. The goals of genomic ARDS studies include better mechanistic understanding, identifying dysregulated pathways that may be amenable to pharmacologic targeting, using genomic causal inference techniques to find measurable traits with meaning, and deconvoluting ARDS heterogeneity by proving reproducible subpopulations that may share a unique biology. This article discusses the latest advances in ARDS genomics, provides historical perspective, and highlights some of the ways that the coronavirus disease 2019 (COVID-19) pandemic is accelerating genomic ARDS research.
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Affiliation(s)
- Heather M Giannini
- University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, 5038 Gates Building, Philadelphia, PA 19104, USA
| | - Nuala J Meyer
- University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, 5038 Gates Building, Philadelphia, PA 19104, USA.
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Sivapalan P, Bonnesen B, Jensen JU. Novel Perspectives Regarding the Pathology, Inflammation, and Biomarkers of Acute Respiratory Distress Syndrome. Int J Mol Sci 2020; 22:E205. [PMID: 33379178 PMCID: PMC7796016 DOI: 10.3390/ijms22010205] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/29/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is an acute inflammation of the lung resulting from damage to the alveolar-capillary membrane, and it is diagnosed using a combination of clinical and physiological variables. ARDS develops in approximately 10% of hospitalised patients with pneumonia and has a mortality rate of approximately 40%. Recent research has identified several biomarkers associated with ARDS pathophysiology, and these may be useful for diagnosing and monitoring ARDS. They may also highlight potential therapeutic targets. This review summarises our current understanding of those clinical biomarkers: (1) biomarkers of alveolar and bronchiolar injury, (2) biomarkers of endothelial damage and coagulation, and (3) biomarkers for treatment responses.
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Affiliation(s)
- Pradeesh Sivapalan
- Respiratory Medicine Section, Department of Internal Medicine, Herlev and Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; (B.B.); (J.-U.J.)
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Zeng Z, Yu H, Chen H, Qi W, Chen L, Chen G, Yan W, Chen T, Ning Q, Han M, Wu D. Longitudinal changes of inflammatory parameters and their correlation with disease severity and outcomes in patients with COVID-19 from Wuhan, China. Crit Care 2020; 24:525. [PMID: 32854750 PMCID: PMC7450961 DOI: 10.1186/s13054-020-03255-0] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/17/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease and rapidly escalating epidemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pathogenesis of COVID-19 remains to be elucidated. We aimed to clarify correlation of systemic inflammation with disease severity and outcomes in COVID-19 patients. METHODS In this retrospective study, baseline characteristics, laboratory findings, and treatments were compared among 317 laboratory-confirmed COVID-19 patients with moderate, severe, or critically ill form of the disease. Moreover, the longitudinal changes of serum cytokines, lactate dehydrogenase (LDH), high-sensitivity C-reactive protein (hsCRP), and hsCRP to lymphocyte count ratio (hsCRP/L) as well as their associations with disease severity and outcomes were investigated in 68 COVID-19 patients. RESULTS Within 24 h of admission, the critically ill patients showed higher concentrations of inflammatory markers including serum soluble interleukin (IL)-2 receptor, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), ferritin, procalcitonin, LDH, hsCRP, and hsCRP/L than patients with severe or moderate disease. The severe cases displayed the similar response patterns when compared with moderate cases. The longitudinal assays showed the levels of pro-inflammatory cytokines, LDH, hsCRP, and hsCRP/L gradually declined within 10 days post admission in moderate, severe cases or those who survived. However, there was no significant reduction in cytokines, LDH, hsCRP, and hsCRP/L levels in critically ill or deceased patients throughout the course of illness. Compared with female patients, male cases showed higher serum concentrations of soluble IL-2R, IL-6, ferritin, procalcitonin, LDH, and hsCRP. Multivariate logistic regression analysis revealed that IL-6 > 50 pg/mL and LDH > 400 U/L on admission were independently associated with disease severity in patients with COVID-19. CONCLUSION Exuberant inflammatory responses within 24 h of admission in patients with COVID-19 may correlate with disease severity. SARS-CoV-2 infection appears to elicit a sex-based differential immune response. IL-6 and LDH were independent predictive parameters for assessing the severity of COVID-19. An early decline of these inflammation markers may be associated with better outcomes.
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Affiliation(s)
- Zhilin Zeng
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Haijing Yu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Huilong Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Weipeng Qi
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Liang Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Guang Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Weiming Yan
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Tao Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Meifang Han
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China.
| | - Di Wu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China.
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Endothelial Protein C Receptor Could Contribute to Experimental Malaria-Associated Acute Respiratory Distress Syndrome. J Immunol Res 2019; 2019:3105817. [PMID: 31871954 PMCID: PMC6913256 DOI: 10.1155/2019/3105817] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 09/26/2019] [Accepted: 10/16/2019] [Indexed: 12/27/2022] Open
Abstract
The severity of Plasmodium falciparum malaria is associated with parasite cytoadherence, but there is limited knowledge about the effect of parasite cytoadherence in malaria-associated acute respiratory distress syndrome (ARDS). Our objective was to evaluate the cytoadherence of infected red blood cells (iRBCs) in a murine model of ARDS and to appraise a potential function of endothelial protein C receptor (EPCR) in ARDS pathogenesis. DBA/2 mice infected with P. berghei ANKA were classified as ARDS- or hyperparasitemia- (HP-) developing mice according to respiratory parameters and parasitemia. Lungs, blood, and bronchoalveolar lavage were collected for gene expression or protein analyses. Primary cultures of microvascular lung endothelial cells from DBA/2 mice were analyzed for iRBC interactions. Lungs from ARDS-developing mice showed evidence of iRBC accumulation along with an increase in EPCR and TNF concentrations. Furthermore, TNF increased iRBC adherence in vitro. Dexamethasone-treated infected mice showed low levels of TNF and EPCR mRNA expression and, finally, decreased vascular permeability, thus protecting mice from ARDS. In conclusion, we identified that increased iRBC cytoadherence in the lungs underlies malaria-associated ARDS in DBA/2-infected mice and that inflammation increased cytoadherence capacity, suggesting a participation of EPCR and a conceivable target for drug development.
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Predictive Value of Combined LIPS and ANG-2 Level in Critically Ill Patients with ARDS Risk Factors. Mediators Inflamm 2018; 2018:1739615. [PMID: 30008611 PMCID: PMC6020511 DOI: 10.1155/2018/1739615] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 04/12/2018] [Accepted: 04/16/2018] [Indexed: 12/21/2022] Open
Abstract
To investigate the predictive value of the acute physiology and chronic health evaluation 2 (APACHE2) score and lung injury prediction score (LIPS) for acute respiratory distress syndrome (ARDS) when combined with biomarkers for this condition in patients with ARDS risk factors. In total, 158 Han Chinese patients with ARDS risk factors were recruited from the Respiratory and Emergency Intensive Care Units. The LIPS, APACHE2 score, primary diagnosis at admission, and ARDS risk factors were determined within 6 h of admission, and PaO2/FiO2 was determined on the day of admission. Blood was collected within 24 h of admission for the measurement of angiopoietin-2 (ANG-2), sE-selectin, interleukin-6 (IL-6), and interleukin-8 (IL-8) levels. ARDS was monitored for the next 7 days. Univariate and multivariate analyses and receiver operating characteristic (ROC) analyses were employed to construct a model for ARDS prediction. Forty-eight patients developed ARDS within 7 days of admission. Plasma ANG-2 level, sE-selectin level, LIPS, and APACHE2 score in ARDS patients were significantly higher than those in non-ARDS patients. ANG-2 level, LIPS, and APACHE2 score were correlated with ARDS (P < 0.001, P < 0.006, and P < 0.042, resp.). When the APACHE2 score was used in combination with the LIPS and ANG-2 level to predict ARDS, the area under the ROC curve (AUC) was not significantly increased. Compared to LIPS or ANG-2 alone, LIPS in combination with ANG-2 had significantly increased positive predictive value (PPV) and AUC for the prediction of ARDS. In conclusion, plasma ANG-2 level, LIPS, and APACHE2 score are correlated with ARDS. Combined LIPS and ANG-2 level displays favorable sensitivity, specificity, and AUC for the prediction of ARDS.
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Liu JS, Wei XD, Lu ZB, Xie P, Zhou HL, Chen YY, Ma JM, Yu LZ. Liang-Ge-San, a classic traditional Chinese medicine formula, protects against lipopolysaccharide-induced inflammation through cholinergic anti-inflammatory pathway. Oncotarget 2018; 7:21222-34. [PMID: 27034013 PMCID: PMC5008280 DOI: 10.18632/oncotarget.8452] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/08/2016] [Indexed: 12/17/2022] Open
Abstract
Liang-Ge-San (LGS) is a classic formula in traditional Chinese medicine, which is widely used to treat acute lung injury (ALI), pharyngitis and amygdalitis in clinic. However, the underlying mechanisms remain poorly defined. In this study, we discovered that LGS exerted potent anti-inflammatory effects in lipopolysaccharide (LPS)-induced inflammation. We found that LGS significantly depressed the production of IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophage cells. The degradation and phosphorylation of IκBα and the nuclear translocation of NF-κB p65 were also inhibited. Moreover, LGS activated α7 nicotinic cholinergic receptor (α7nAchR). The blockage of α7nAchR by selective inhibitor methyllycaconitine (MLA) or α7nAchR siRNA attenuated the inhibitory effects of LGS on IκBα, NF-κB p65, IL-6 and TNF-α. Critically, LGS significantly inhibited inflammation in LPS-induced ALI rats through the activation of NF-κB signaling pathway. However, these protective effects could be counteracted by the treatment of MLA. Taken together, we first demonstrated anti-inflammatory effects of LGS both in vitro and in vivo through cholinergic anti-inflammatory pathway. The study provides a rationale for the clinical application of LGS as an anti-inflammatory agent and supports the critical role of cholinergic anti-inflammatory pathway in inflammation.
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Affiliation(s)
- Jun-Shan Liu
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Xi-Duan Wei
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Zi-Bin Lu
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Pei Xie
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Hong-Ling Zhou
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Yu-Yao Chen
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Jia-Mei Ma
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
| | - Lin-Zhong Yu
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, P. R. China
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Kuuliala K, Penttilä AK, Kaukonen KM, Mustonen H, Kuuliala A, Oiva J, Hämäläinen M, Moilanen E, Pettilä V, Puolakkainen P, Kylänpää L, Repo H. Signalling Profiles of Blood Leucocytes in Sepsis and in Acute Pancreatitis in Relation to Disease Severity. Scand J Immunol 2017; 87:88-98. [DOI: 10.1111/sji.12630] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/03/2017] [Indexed: 12/14/2022]
Affiliation(s)
- K. Kuuliala
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - A. K. Penttilä
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - K.-M. Kaukonen
- Department of Anesthesiology, Intensive Care and Pain Medicine; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - H. Mustonen
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - A. Kuuliala
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - J. Oiva
- Department of Surgery; Kuopio University Hospital; Kuopio Finland
| | - M. Hämäläinen
- The Immunopharmacology Research Group; Faculty of Medicine and Life Sciences; University of Tampere and Tampere University Hospital; Tampere Finland
| | - E. Moilanen
- The Immunopharmacology Research Group; Faculty of Medicine and Life Sciences; University of Tampere and Tampere University Hospital; Tampere Finland
| | - V. Pettilä
- Department of Anesthesiology, Intensive Care and Pain Medicine; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - P. Puolakkainen
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - L. Kylänpää
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - H. Repo
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
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Plasma Concentrations of Soluble Suppression of Tumorigenicity-2 and Interleukin-6 Are Predictive of Successful Liberation From Mechanical Ventilation in Patients With the Acute Respiratory Distress Syndrome. Crit Care Med 2017; 44:1735-43. [PMID: 27525994 DOI: 10.1097/ccm.0000000000001814] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVES Soluble suppression of tumorigenicity-2 and interleukin-6 concentrations have been associated with the inflammatory cascade of acute respiratory distress syndrome. We determined whether soluble suppression of tumorigenicity-2 and interleukin-6 levels can be used as prognostic biomarkers to guide weaning from mechanical ventilation and predict the need for reintubation. DESIGN, SETTING, AND PATIENTS We assayed plasma soluble suppression of tumorigenicity-2 (n = 826) concentrations and interleukin-6 (n = 755) concentrations in the Fluid and Catheter Treatment Trial, a multicenter randomized controlled trial of conservative fluid management in acute respiratory distress syndrome. We tested whether soluble suppression of tumorigenicity-2 and interleukin-6 levels were associated with duration of mechanical ventilation, the probability of passing a weaning assessment, and the need for reintubation. MEASUREMENTS AND MAIN RESULTS In models adjusted for Acute Physiology and Chronic Health Evaluation score and other relevant variables, patients with higher day 0 and day 3 median soluble suppression of tumorigenicity-2 and interleukin-6 concentrations had decreased probability of extubation over time (day 0 soluble suppression of tumorigenicity-2: hazard ratio, 0.85; 95% CI, 0.72-1.00; p = 0.05; day 0 interleukin-6: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; day 3 soluble suppression of tumorigenicity-2: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; and day 3 interleukin-6: hazard ratio, 0.73; 95% CI, 0.62-0.85; p = 0.0001). Higher biomarker concentrations were also predictive of decreased odds of passing day 3 weaning assessments (soluble suppression of tumorigenicity-2: odds ratio, 0.62: 95% CI, 0.44-0.87; p = 0.006 and interleukin-6: odds ratio, 0.61; 95% CI, 0.43-0.85; p = 0.004) and decreased odds of passing a spontaneous breathing trial (soluble suppression of tumorigenicity-2: odds ratio, 0.45; 95% CI, 0.28-0.71; p = 0.0007 and interleukin-6 univariate analysis only: odds ratio, 0.55; 95% CI, 0.36-0.83; p = 0.005). Finally, higher biomarker levels were significant predictors of the need for reintubation for soluble suppression of tumorigenicity-2 (odds ratio, 3.23; 95% CI, 1.04-10.07; p = 0.04) and for interleukin-6 (odds ratio, 2.58; 95% CI, 1.14-5.84; p = 0.02). CONCLUSIONS Higher soluble suppression of tumorigenicity-2 and interleukin-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with acute respiratory distress syndrome. Biomarker-directed ventilator management may lead to improved outcomes in weaning of mechanical ventilation in patients with acute respiratory distress syndrome.
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Yang CH, Hsiao JL, Wu MF, Lu MH, Chang HM, Ko WS, Chiou YL. The declined levels of inflammatory cytokines related with weaning rate during period of septic patients using ventilators. CLINICAL RESPIRATORY JOURNAL 2016; 12:772-778. [PMID: 27925446 DOI: 10.1111/crj.12593] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 11/04/2016] [Accepted: 11/11/2016] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Approximately 50% of patients with sepsis-induced acute lung injury and acute respiratory distress syndrome require mechanical ventilation. Patients with extended mechanical ventilator use routinely develop reinfections, which increases hospital stay, mortality, and health care cost. Some studies have pointed out inflammatory factors concentrations can affect ventilator weaning, but do not indicate changed inflammatory factors related to ventilator weaning during using ventilators. OBJECTIVES This study aimed to investigate during period of septic patients using ventilators, the inflammatory cytokines concentrations related with weaning rate. METHODS Blood was collected from 35 septic patients before and during ventilator use on days 1, 7, 14, and 21 (or weaning). RESULTS 58.3% (N = 20) of septic patients with mechanical ventilators were weaned successfully within 21 days (ventilator weaned group, VW), 16.7% (N = 6) did not wean within 21 days (ventilator dependent group, VD), and 25% died (death group) in hospital. Before ventilator use, higher C-reactive protein (CRP), IL-6, and IL-8 levels were measured in the death group than in all other groups (P < .05). During ventilator use, CRP, IL-6, and IL-8 concentrations declined significantly in VW and VD patients (P < .05). In addition, IL-6 concentrations in the VW group were significantly lower than in the VD group at 14 and 21 days (P < .05). CONCLUSION The factors of ventilators weaning successfully such as disease control, nutritional status, and so on. The declined levels of serum inflammatory cytokines, especially IL-6, improved inflammation status might be one factor of successfully weaning during septic patients on ventilators.
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Affiliation(s)
- Chao-Huei Yang
- Department of Pulmonary Medicine, Kuang-Tien General Hospital, Taichung, Taiwan, Republic of China
| | - Jung-Lung Hsiao
- Department of Critical Care Medicine, Kuang-Tien General Hospital, Taichung, Taiwan, Republic of China
| | - Ming-Feng Wu
- Department of Internal Medicine, Kuang-Tien General Hospital, Taichung, Taiwan, Republic of China
| | - Mei-Hua Lu
- Department of Nursing, Kuang-Tien General Hospital, Taichung, Taiwan, Republic of China
| | - Hui-Ming Chang
- Department of Nursing, Kuang-Tien General Hospital, Taichung, Taiwan, Republic of China
| | - Wang-Sheng Ko
- Department of Internal Medicine, Kuang-Tien General Hospital, Taichung, Taiwan, Republic of China.,Department of Nutrition and Institute of BioMedical Nutrition, Hungkuang University, Taichung, Taiwan, Republic of China
| | - Ya-Ling Chiou
- Department of Nutrition and Institute of BioMedical Nutrition, Hungkuang University, Taichung, Taiwan, Republic of China
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Swaroopa D, Bhaskar K, Mahathi T, Katkam S, Raju YS, Chandra N, Kutala VK. Association of serum interleukin-6, interleukin-8, and Acute Physiology and Chronic Health Evaluation II score with clinical outcome in patients with acute respiratory distress syndrome. Indian J Crit Care Med 2016; 20:518-25. [PMID: 27688627 PMCID: PMC5027744 DOI: 10.4103/0972-5229.190369] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background and Aim: Studies on potential biomarkers in experimental models of acute lung injury (ALI) and clinical samples from patients with ALI have provided evidence to the pathophysiology of the mechanisms of lung injury and predictor of clinical outcome. Because of the high mortality and substantial variability in outcomes in patients with acute respiratory distress syndrome (ARDS), identification of biomarkers such as cytokines is important to determine prognosis and guide clinical decision-making. Materials and Methods: In this study, we have included thirty patients admitted to Intensive Care Unit diagnosed with ARDS, and serum samples were collected on day 1 and 7 and were analyzed for serum interleukin-6 (IL-6) and IL-8 by ELISA method, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring was done on day 1. Results: The mortality in the patients observed with ARDS was 34%. APACHE II score was significantly higher in nonsurvivors as compared to survivors. There were no significant differences in gender and biochemical and hematological parameters among the survivors and nonsurvivors. Serum IL-6 and IL-8 levels on day 1 were significantly higher in all the ARDS patients as compared to healthy controls and these levels were returned to near-normal basal levels on day 7. The serum IL-6 and IL-8 levels measured on day 7 were of survivors. As compared to survivors, the IL-6 and IL-8 levels were significantly higher in nonsurvivors measured on day 1. Spearman's rank correlation analysis indicated a significant positive correlation of APACHE II with IL-8. By using APACHE II score, IL-6, and IL-8, the receiver operating characteristic curve was plotted and the provided predictable accuracy of mortality (outcome) was 94%. Conclusion: The present study highlighted the importance of measuring the cytokines such as IL-6 and IL-8 in patients with ARDS in predicting the clinical outcome.
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Affiliation(s)
- Deme Swaroopa
- Department of General Medicine, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Kakarla Bhaskar
- Department of Respiratory Medicine, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - T Mahathi
- Department of General Medicine, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Shivakrishna Katkam
- Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Y Satyanarayana Raju
- Department of General Medicine, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Naval Chandra
- Department of General Medicine, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
| | - Vijay Kumar Kutala
- Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
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Halacli B, Unver N, Halacli SO, Canpinar H, Ersoy EO, Ocal S, Guc D, Buyukasik Y, Topeli A. Investigation of hemophagocytic lymphohistiocytosis in severe sepsis patients. J Crit Care 2016; 35:185-90. [PMID: 27481757 DOI: 10.1016/j.jcrc.2016.04.034] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 04/07/2016] [Accepted: 04/27/2016] [Indexed: 12/24/2022]
Abstract
PURPOSE Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by uncontrolled inflammation and has common clinical and laboratory features with sepsis. The aim of this study was to investigate patients treated with severe sepsis who had bicytopenia for the presence of HLH. MATERIALS AND METHODS Patients with severe sepsis who were non-responsive to treatment and developed at least bicytopenia were included. Peripheral blood samples were collected and stored for later evaluation for natural killer (NK) activity and soluble interleukin-2 receptor levels. Diagnostic criteria of HLH were retrospectively analyzed. RESULTS Seventy-five of 382 patients (20%) were followed as severe sepsis and septic shock. Among them, 40 patients had bicytopenia. Twenty-six of 40 patients were excluded due to the presence of active solid or hematological malignancies. Three patients died before fulfillment of HLH criteria and one patient denied to give consent. All of the remaining 10 patients had at least five of the eight criteria according to criteria of the Histiocyte Society. Only one of 10 patients was diagnosed as HLH and received treatment during intensive care unit stay. None of the 10 patients survived. CONCLUSIONS This study emphasizes to consider the possibility of HLH and the need of rapid assessment of patients with severe sepsis who had bicytopenia and were resistant to treatment in intensive care.
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Affiliation(s)
- Burcin Halacli
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Medical Intensive Care Unit, Ankara, Turkey.
| | - Nese Unver
- The University of Texas, MD Anderson Cancer Center, Houston, USA.
| | - Sevil Oskay Halacli
- Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Immunology, Ankara, Turkey.
| | - Hande Canpinar
- Hacettepe University Faculty of Medicine, Department of Basic Oncology, Ankara, Turkey.
| | - Ebru Ortac Ersoy
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Medical Intensive Care Unit, Ankara, Turkey.
| | - Serpil Ocal
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Medical Intensive Care Unit, Ankara, Turkey.
| | - Dicle Guc
- Hacettepe University Faculty of Medicine, Department of Basic Oncology, Ankara, Turkey.
| | - Yahya Buyukasik
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey.
| | - Arzu Topeli
- Hacettepe University Faculty of Medicine, Department of Internal Medicine, Medical Intensive Care Unit, Ankara, Turkey.
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Abstract
The unique characteristics of pulmonary circulation and alveolar-epithelial capillary-endothelial barrier allow for maintenance of the air-filled, fluid-free status of the alveoli essential for facilitating gas exchange, maintaining alveolar stability, and defending the lung against inhaled pathogens. The hallmark of pathophysiology in acute respiratory distress syndrome is the loss of the alveolar capillary permeability barrier and the presence of protein-rich edema fluid in the alveoli. This alteration in permeability and accumulation of fluid in the alveoli accompanies damage to the lung epithelium and vascular endothelium along with dysregulated inflammation and inappropriate activity of leukocytes and platelets. In addition, there is uncontrolled activation of coagulation along with suppression of fibrinolysis and loss of surfactant. These pathophysiological changes result in the clinical manifestations of acute respiratory distress syndrome, which include hypoxemia, radiographic opacities, decreased functional residual capacity, increased physiologic deadspace, and decreased lung compliance. Resolution of acute respiratory distress syndrome involves the migration of cells to the site of injury and re-establishment of the epithelium and endothelium with or without the development of fibrosis. Most of the data related to acute respiratory distress syndrome, however, originate from studies in adults or in mature animals with very few studies performed in children or juvenile animals. The lack of studies in children is particularly problematic because the lungs and immune system are still developing during childhood and consequently the pathophysiology of pediatric acute respiratory distress syndrome may differ in significant ways from that seen in acute respiratory distress syndrome in adults. This article describes what is known of the pathophysiologic processes of pediatric acute respiratory distress syndrome as we know it today while also presenting the much greater body of evidence on these processes as elucidated by adult and animal studies. It is also our expressed intent to generate enthusiasm for larger and more in-depth investigations of the mechanisms of disease and repair specific to children in the years to come.
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Plasma angiopoietin 2 concentrations are related to impaired lung function and organ failure in a clinical cohort receiving high-dose interleukin 2 therapy. Shock 2015; 42:115-20. [PMID: 24727870 DOI: 10.1097/shk.0000000000000188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High-dose interleukin 2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In preclinical models, IL-2 stimulates angiopoietin 2 (AngP-2) secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Furthermore, the relevance of plasma AngP-2 to organ function is not clear. We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical pathophysiology. METHODS We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2 and collected blood and spirometry data daily. The plasma concentrations of AngP-2 and IL-6 were measured with enzyme-linked immunosorbent assay. RESULTS At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL. Angiopoietin 2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 (SD, 4.5) ng/mL and increased further to 18.6 (SD, 4.9) ng/mL (P < 0.05 vs. penultimate) during the last day of therapy. The forced expiratory volume in 1 s decreased during treatment. Interestingly, plasma AngP-2 concentrations correlated negatively with forced expiratory volume in 1 s (Spearman r = -0.78, P < 0.0001). Plasma AngP-2 concentrations also correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001) and Sequential Organ Failure Assessment scores (r = 0.68, P < 0.0001). CONCLUSIONS Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with pulmonary dysfunction. High-dose IL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.
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Goldman JL, Sammani S, Kempf C, Saadat L, Letsiou E, Wang T, Moreno-Vinasco L, Rizzo AN, Fortman JD, Garcia JGN. Pleiotropic effects of interleukin-6 in a "two-hit" murine model of acute respiratory distress syndrome. Pulm Circ 2014; 4:280-8. [PMID: 25006447 DOI: 10.1086/675991] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 01/09/2014] [Indexed: 12/19/2022] Open
Abstract
Patients with acute respiratory distress syndrome (ARDS) exhibit elevated levels of interleukin-6 (IL-6), which correlate with increased morbidity and mortality. The exact role of IL-6 in ARDS has proven difficult to study because it exhibits either pro- or anti-inflammatory actions in mouse models of lung injury, depending on the model utilized. In order to improve understanding of the role of this complex cytokine in ARDS, we evaluated IL-6 using the clinically relevant combination of lipopolysaccharide (LPS) and ventilator-induced lung injury (VILI) in IL-6(-/-) mice. Bronchoalveolar lavage fluid (BAL), whole-lung tissue, and histology were evaluated for inflammatory markers of injury. Transendothelial electrical resistance was used to evaluate the action of IL-6 on endothelial cells in vitro. In wild-type mice, the combination model showed a significant increase in lung injury compared to either LPS or VILI alone. IL-6(-/-) mice exhibited a statistically significant decrease in BAL cellular inflammation as well as lower histologic scores for lung injury, changes observed only in the combination model. A paradoxical increase in BAL total protein was observed in IL-6(-/-) mice exposed to LPS, suggesting that IL-6 provides protection from vascular leakage. However, in vitro data showed that IL-6, when combined with its soluble receptor, actually caused a significant increase in endothelial cell permeability, suggesting that the protection seen in vivo was likely due to complex interactions of IL-6 and other inflammatory mediators rather than to direct effects of IL-6. These studies suggest that a dual-injury model exhibits utility in evaluating the pleiotropic effects of IL-6 in ARDS on inflammatory cells and lung endothelium.
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Affiliation(s)
- Julia L Goldman
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Biological Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Saad Sammani
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Carrie Kempf
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Current affiliation: Division of Pulmonary and Critical Care, Sleep Medicine, Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA
| | - Laleh Saadat
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Eleftheria Letsiou
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ting Wang
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Current affiliation: Division of Pulmonary and Critical Care, Sleep Medicine, Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA
| | - Liliana Moreno-Vinasco
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Alicia N Rizzo
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jeffrey D Fortman
- Biological Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Joe G N Garcia
- Institute of Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois, USA ; Office of the Vice President for Health Affairs, University of Illinois at Chicago, Chicago, Illinois, USA ; Current affiliation: Division of Pulmonary and Critical Care, Sleep Medicine, Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA
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Plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis*. Crit Care Med 2014; 42:691-700. [PMID: 24158164 DOI: 10.1097/01.ccm.0000435669.60811.24] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Numerous studies have focused on biomarkers for acute lung injury and acute respiratory distress syndrome. Although several biomarkers have been identified, their relative performance is unclear. We aim to provide a quantitative overview of plasma-derived biomarkers associated with acute respiratory distress syndrome diagnosis or mortality. DATA SOURCES MEDLINE (inception to January 2012) and personal databases. STUDY SELECTION English-language studies on plasma biomarkers associated with acute respiratory distress syndrome diagnosis or mortality. DATA EXTRACTION Demographic variables, plasma levels of biomarker, statistical data, acute respiratory distress syndrome occurrence, and mortality rates were retrieved. The methodological quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies score. Clinical outcomes included 1) diagnosis of acute respiratory distress syndrome in the at-risk population and 2) mortality in acute respiratory distress syndrome patients. For each biomarker, pooled odds ratios for clinical outcome were calculated by meta-analysis, and biomarkers were ranked according to pooled odds ratio. DATA SYNTHESIS Fifty-four studies appeared eligible for meta-analysis, together including 3,753 patients. We identified 20 biomarkers for diagnosis of acute respiratory distress syndrome in the at-risk population and 19 biomarkers for mortality of acute respiratory distress syndrome patients. The biomarkers most strongly associated with acute respiratory distress syndrome diagnosis in the at-risk population, when increased, were Krebs von den Lungen-6 (odds ratio [95% CI], 6.1 [3.0-12.1]), lactate dehydrogenase (5.7 [1.7-19.1]), soluble receptor for advanced glycation end products (3.5 [1.7-7.2]), and von Willebrand Factor (3.1 [2.0-5.2]). The biomarkers most strongly associated with acute respiratory distress syndrome mortality, when increased, were interleukin-4 (18.0 [6.0-54.2]), interleukin-2 (11.8 [4.3-32.2]), angiopoietin-2 (6.4 [1.3-30.4]), and Krebs von den Lungen-6 (5.1 [3.0-12.2]). Decreased levels of Protein C were associated with increased odds for acute respiratory distress syndrome diagnosis and mortality. CONCLUSIONS This meta-analysis provides a unique ranking of plasma biomarkers according to their strength of association with acute respiratory distress syndrome diagnosis or acute respiratory distress syndrome mortality. The relative performance of biomarkers among studies shown in this ranking may help to improve acute respiratory distress syndrome diagnosis and outcome prediction.
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Morrison JJ, Ross JD, Markov NP, Scott DJ, Spencer JR, Rasmussen TE. The inflammatory sequelae of aortic balloon occlusion in hemorrhagic shock. J Surg Res 2014; 191:423-31. [PMID: 24836421 DOI: 10.1016/j.jss.2014.04.012] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Revised: 03/11/2014] [Accepted: 04/04/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a hemorrhage control and resuscitative adjunct that has been demonstrated to improve central perfusion during hemorrhagic shock. The aim of this study was to characterize the systemic inflammatory response associated and cardiopulmonary sequelae with 30, 60, and 90 min of balloon occlusion and shock on the release of interleukin 6 (IL-6) and tumor necrosis factor alpha. MATERIALS AND METHODS Anesthetized female Yorkshire swine (Sus scrofa, weight 70-90 kg) underwent a 35% blood volume-controlled hemorrhage followed by thoracic aortic balloon occlusion of 30 (30-REBOA, n = 6), 60 (60-REBOA, n = 8), and 90 min (90-REBOA, n = 6). This was followed by resuscitation with whole blood and crystalloid over 6 h. Animals then underwent 48 h of critical care with sedation, fluid, and vasopressor support. RESULTS All animals were successfully induced into hemorrhagic shock without mortality. All groups responded to aortic occlusion with a rise in blood pressure above baseline values. IL-6, as measured (picogram per milliliter) at 8 h, was significantly elevated from baseline values in the 60-REBOA and 90-REBOA groups: 289 ± 258 versus 10 ± 5; P = 0.018 and 630 ± 348; P = 0.007, respectively. There was a trend toward greater vasopressor use (P = 0.183) and increased incidence of acute respiratory distress syndrome (P = 0.052) across the groups. CONCLUSIONS REBOA is a useful adjunct in supporting central perfusion during hemorrhagic shock; however, increasing occlusion time and shock results in a greater IL-6 release. Clinicians must anticipate inflammation-mediated organ failure in post-REBOA use patients.
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Affiliation(s)
- Jonathan J Morrison
- The Academic Department of Military Surgery & Trauma, Royal Centre for Defence Medicine, Birmingham, United Kingdom; The United States Army Institute of Surgical Research, Fort Sam Houston, Texas; Academic Unit of Surgery, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - James D Ross
- 59th Medical Wing, Joint Base San Antonio, Lackland, Texas
| | - Nickolay P Markov
- The United States Army Institute of Surgical Research, Fort Sam Houston, Texas
| | - Daniel J Scott
- The United States Army Institute of Surgical Research, Fort Sam Houston, Texas; 59th Medical Wing, Joint Base San Antonio, Lackland, Texas
| | | | - Todd E Rasmussen
- The United States Army Institute of Surgical Research, Fort Sam Houston, Texas; 59th Medical Wing, Joint Base San Antonio, Lackland, Texas; The Norman M. Rich Department of Surgery, the Uniformed Services University of the Health Sciences, Bethesda, Maryland.
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Park SY, Seetharaman R, Ko MJ, Kim DY, Kim TH, Yoon MK, Kwak JH, Lee SJ, Bae YS, Choi YW. Ethyl linoleate from garlic attenuates lipopolysaccharide-induced pro-inflammatory cytokine production by inducing heme oxygenase-1 in RAW264.7 cells. Int Immunopharmacol 2014; 19:253-61. [DOI: 10.1016/j.intimp.2014.01.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 01/14/2014] [Accepted: 01/17/2014] [Indexed: 12/25/2022]
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Li T, Luo N, Du L, Zhou J, Zhang J, Gong L, Jiang N. Tumor necrosis factor-α plays an initiating role in extracorporeal circulation-induced acute lung injury. Lung 2013; 191:207-14. [PMID: 23355084 DOI: 10.1007/s00408-012-9449-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 12/24/2012] [Indexed: 02/05/2023]
Abstract
BACKGROUND Despite advances in critical care, the mortality rate for patients with acute lung injury (ALI) remains high. The aim of this study was to test the hypothesis that tumor necrosis factor-α (TNF-α) plays an initiating role in the onset of extracorporeal circulation (ECC)-induced ALI. METHODS Eight New Zealand rabbits subjected to 1 h of ECC and 40 min of observation after termination of ECC were used for monitoring pulmonary nociceptor activity. Fifty Sprague-Dawley (SD) rats that received 2 h of ECC and 4 h of rest were used to measure the pulmonary function and inflammatory cytokines release, including total cells, neutrophils, and TNF-α in bronchoalveolar lavage (BAL) and white blood cell (WBC) and neutrophils in blood. An additional 40 SD rats were randomized to pretreatment with inhalation of phosphate buffer solution (control group), IgG (IgG inh group), or TNF-α antibody (anti-TNF-α inh group) and venous injection of TNF-α antibody (anti-TNF-α iv group). After 2 h of ECC and 4 h of rest, the arterial blood and BAL fluid were collected for measurement of arterial oxygen pressure (PaO2) and inflammatory cytokines release. The left-lower-lung tissues of animals were stained with hematoxylin & eosin (H&E). RESULTS The results demonstrated that the activities of airway nociceptor and TNF-α release were similarly upregulated at the early stage and in a time-related manner in ECC-induced ALI. Pretreatment with TNF-α antibody inhalation, but not venous injection, improved pulmonary function, inhibited pulmonary inflammation, and attenuated pulmonary histopathological changes after ECC. CONCLUSION We concluded that TNF-α played an important role in the pathogenesis of ALI and acted as an initiating cytokine at the early stage of ECC-induced ALI.
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Affiliation(s)
- Tao Li
- Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, China
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Oiva J, Mustonen H, Kylänpää ML, Kuuliala K, Siitonen S, Kemppainen E, Puolakkainen P, Repo H. Patients with acute pancreatitis complicated by organ dysfunction show abnormal peripheral blood polymorphonuclear leukocyte signaling. Pancreatology 2013; 13:118-24. [PMID: 23561969 DOI: 10.1016/j.pan.2013.01.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 01/24/2013] [Accepted: 01/25/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Circulating polymorphonuclear leukocytes (PMNLs) may contribute to development of organ dysfunction in acute pancreatitis (AP). We outlined aberrations in PMNL signaling profiles in patients with AP complicated by organ dysfunction and immune suppression. METHODS Study comprised 13 patients treated at intensive care unit due to severe AP complicated by vital organ dysfunction. Mean proportion (SEM) of HLA-DR-positive monocytes was 55.0% (4.1%). 13 healthy volunteers served as reference subjects. Phosphorylation of PMNL NFκB, p38, ERK1/2 and STAT3, -5 and -6 was determined using whole blood flow cytometry. Transmigration of PMNLs was studied using endothelial EA-HY cell monolayer. RESULTS Proportions of NFκB phosphorylation-positive PMNLs were lower in the patients' than in reference subjects' blood samples supplemented with tumor necrosis factor. p38 phosphorylation was normal while ERK1/2 phosphorylation was decreased. STAT3 was constitutively activated in five patients. Proportion of patients' pSTAT6-positive cells was normal while fluorescence intensity was decreased. STAT5 phosphorylation was normal. Transmigration of patients' PMNLs was increased. CONCLUSIONS In patients with AP complicated by organ dysfunction proportion of pNFκB-positive PMNLs is decreased. This impairs patients' defense mechanisms against infection. Despite immune suppression, PMNL transmigration was increased and p38 phosphorylation capacity was not depressed, which may contribute to end organ inflammation and dysfunction.
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Affiliation(s)
- Jani Oiva
- Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland
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Gonçalves-de-Albuquerque CF, Silva AR, Burth P, de Moraes IMM, Oliveira FMDJ, Younes-Ibrahim M, dos Santos MDCB, D'Ávila H, Bozza PT, Faria Neto HCDC, Faria MVDC. Oleic acid induces lung injury in mice through activation of the ERK pathway. Mediators Inflamm 2012; 2012:956509. [PMID: 23209347 PMCID: PMC3504460 DOI: 10.1155/2012/956509] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 10/18/2012] [Indexed: 01/06/2023] Open
Abstract
Oleic acid (OA) can induce acute lung injury in experimental models. In the present work, we used intratracheal OA injection to show augmented oedema formation, cell migration and activation, lipid mediator, and cytokine productions in the bronchoalveolar fluids of Swiss Webster mice. We also demonstrated that OA-induced pulmonary injury is dependent on ERK1/2 activation, since U0126, an inhibitor of ERK1/2 phosphorylation, blocked neutrophil migration, oedema, and lipid body formation as well as IL-6, but not IL-1β production. Using a mice strain carrying a null mutation for the TLR4 receptor, we proved that increased inflammatory parameters after OA challenges were not due to the activation of the TLR4 receptor. With OA being a Na/K-ATPase inhibitor, we suggest the possible involvement of this enzyme as an OA target triggering lung inflammation.
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Li T, Zhang Z, Wu W, Liao D, Chen Y, Li S, Yang C, Xu X, Liu J. Resuscitation with polymerized human placenta hemoglobin attenuated hemorrhagic shock-induced lung injury. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2012; 41:27-31. [PMID: 22947048 DOI: 10.3109/10731199.2012.696061] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
This study was designed to investigate whether polymerized human placenta hemoglobin (PolyPHb) attenuated hemorrhagic shock-induced lung injury. A mean arterial pressure (MAP) of 30mmHg was maintained for 60 min. Then, all the rats were randomly resuscitated with hetastarch, whole blood, or PolyPHb. The result indicated that PolyPHb greatly improved the MAP and pulmonary function, and significantly reduced the release of inflammatory cytokines, histopathological changes, and pulmonary edema. Therefore, our findings suggest that PolyPHb could reduce pulmonary injury after hemorrhagic shock, and this effect was probably associated with the depressed inflammatory response.
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Affiliation(s)
- Tao Li
- Laboratory of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
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Bhargava M, Wendt CH. Biomarkers in acute lung injury. Transl Res 2012; 159:205-17. [PMID: 22424425 PMCID: PMC4537856 DOI: 10.1016/j.trsl.2012.01.007] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 01/06/2012] [Accepted: 01/08/2012] [Indexed: 01/11/2023]
Abstract
Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) result in high permeability pulmonary edema causing hypoxic respiratory failure with high morbidity and mortality. As the population ages, the incidence of ALI is expected to rise. Over the last decade, several studies have identified biomarkers in plasma and bronchoalveolar lavage fluid providing important insights into the mechanisms involved in the pathophysiology of ALI. Several biomarkers have been validated in subjects from the large, multicenter ARDS clinical trials network. Despite these studies, no single or group of biomarkers has made it into routine clinical practice. New high throughput "omics" techniques promise improved understanding of the biologic processes in the pathogenesis in ALI and possibly new biomarkers that predict disease and outcomes. In this article, we review the current knowledge on biomarkers in ALI.
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Affiliation(s)
- Maneesh Bhargava
- Pulmonary and Critical Care Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN 55417, USA
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Raymondos K, Martin MU, Schmudlach T, Baus S, Weilbach C, Welte T, Krettek C, Frink M, Hildebrand F. Early alveolar and systemic mediator release in patients at different risks for ARDS after multiple trauma. Injury 2012; 43:189-95. [PMID: 21703617 DOI: 10.1016/j.injury.2011.05.034] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Accepted: 05/25/2011] [Indexed: 02/02/2023]
Abstract
Alveolar IL-8 has been reported to early identify patients at-risk to develop ARDS. However, it remains unknown how alveolar IL-8 is related to pulmonary and systemic inflammation in patients predisposed for ARDS. We studied 24 patients 2-6h after multiple trauma. Patients with IL-8 >200 pg/ml in bronchoalveolar lavage (BAL) were assigned to the group at high risk for ARDS (H, n = 8) and patients with BAL IL-8 <200 pg/ml to the group at low risk for ARDS (L, n = 16). ARDS developed within 24h after trauma in 5 patients at high and at least after 1 week in 2 patients at low risk for ARDS (p = 0.003). High-risk patients had also increased BAL IL-6, TNF-α, IL-1β, IL-10 and IL-1ra levels (p<0.05). BAL neutrophil counts did not differ between patient groups (H vs. L, 12% (3-73%) vs. 6% (2-32%), p = 0.1) but correlated significantly with BAL IL-8, IL-6 and IL-1ra. High-risk patients had increased plasma levels of pro- but not anti-inflammatory mediators. The enhanced alveolar and systemic inflammation associated with alveolar IL-8 release should be considered to identify high-risk patients for pulmonary complications after multiple trauma to adjust surgical and other treatment strategies to the individual risk profile.
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Abstract
Activation of the cholinergic anti-inflammatory pathway through direct activation of nicotinic acetylcholine receptors on immune cells can inhibit pro-inflammatory chemokine and cytokine release and thereby protect in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against acute lung inflammation. Mice challenged with intratracheal lipopolysaccharide (LPS, 50 μg) were treated with nicotine (0.2 or 0.4 mg/kg, sc). After 24 h, bronchoalveolar lavage fluid (BALF) was obtained to measure leukocyte infiltration, lung edema, and pro-inflammatory chemokine (MIP-1α, MIP-2, and eotaxin) and cytokine (IL-1, IL-6, and TNF-α) levels. Nicotine treatment reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by decreased BALF inflammatory cells, myeloperoxidase, and protein. Nicotine also downregulated lung production of pro-inflammatory chemokines and cytokines. These data support the proposal that activation of the cholinergic anti-inflammatory pathway may represent a useful addition to the therapy of acute respiratory distress syndrome.
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Affiliation(s)
- Jon Mabley
- School of Pharmacy & Biomolecular Sciences, University of Brighton, Brighton BN2 4GJ, UK.
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Abstract
This article reviews the state of the art regarding biomarkers for prediction, diagnosis, and prognosis in acute lung injury. Biomarkers and the goals of biomarker research are defined. Progress along 4 general routes is examined. First, the results of wide-ranging existing protein biomarkers are reported. Second, newer biomarkers awaiting or with strong potential for validation are described. Third, progress in the fields of genomics and proteomics is reported. Finally, given the complexity and number of potential biomarkers, the results of combining clinical predictors with protein and other biomarkers to produce better prognostic and diagnostic indices are examined.
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Affiliation(s)
- Nicolas Barnett
- Research Fellow, Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee
| | - Lorraine B. Ware
- Associate Professor of Medicine, Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee
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Relationship Between HMGB1 and Tissue Protective Effects of HSP72 in a LPS-Induced Systemic Inflammation Model. J Surg Res 2011; 169:85-91. [DOI: 10.1016/j.jss.2009.10.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Revised: 09/05/2009] [Accepted: 10/08/2009] [Indexed: 11/17/2022]
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Yuan JXJ, Garcia JG, West JB, Hales CA, Rich S, Archer SL. Genomics of Acute Lung Injury and Vascular Barrier Dysfunction. TEXTBOOK OF PULMONARY VASCULAR DISEASE 2011. [PMCID: PMC7122529 DOI: 10.1007/978-0-387-87429-6_63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Acute lung injury (ALI) is a devastating syndrome of diffuse alveolar damage that develops via a variety of local and systemic insults such as sepsis, trauma, pneumonia, and aspiration. It is interestingly to note that only a subset of individuals exposed to potential ALI-inciting insults develop the disorder and the severity of the disease varies from complete resolution to death. In addition, ALI susceptibility and severity are also affected by ethnicity as evidenced by the higher mortality rates observed in African-American ALI patients compared with other ethnic groups in the USA. Moreover, marked differences in strain-specific ALI responses to inflammatory and injurious agents are observed in preclinical animal models. Together, these observations strongly indicate genetic components to be involved in the pathogenesis of ALI. The identification of genes contributing to ALI would potentially provide a better understanding of ALI pathobiology, yield novel biomarkers, identify individuals or populations at risk, and prove useful for the development of novel and individualized therapies. Genome-wide searches in animal models have identified a number of quantitative trait loci that associate with ALI susceptibility. In this chapter, we utilize a systems biology approach combining cellular signaling pathway analysis with population- based association studies to review established and suspected candidate genes that contribute to dysfunction of endothelial cell barrier integrity and ALI susceptibility.
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Affiliation(s)
- Jason X. -J. Yuan
- Departments of Medicine, COMRB Rm. 3131 (MC 719), University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, 60612 Illinois USA
| | - Joe G.N. Garcia
- 310 Admin.Office Building (MC 672), University of Illinois at Chicago, 1737 W. Polk Street, Suite 310, Chicago, 60612 Illinois USA
| | - John B. West
- Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0623 California USA
| | - Charles A. Hales
- Dept. Pulmonary & Critical Care Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114 Massachusetts USA
| | - Stuart Rich
- Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Ave., Chicago, 60637 Illinois USA
| | - Stephen L. Archer
- Department of Medicine, University of Chicago School of Medicine, 5841 S. Maryland Ave., Chicago, 60637 Illinois USA
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Erythropoetin as a novel agent with pleiotropic effects against acute lung injury. Eur J Clin Pharmacol 2010; 67:1-9. [PMID: 21069520 DOI: 10.1007/s00228-010-0938-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Accepted: 09/28/2010] [Indexed: 12/14/2022]
Abstract
Current pharmacotherapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is not optimal, and the biological and physiological complexity of these severe lung injury syndromes requires consideration of combined-agent treatments or agents with pleiotropic action. In this regard, exogenous erythropoietin (EPO) represents a possible candidate since a number of preclinical studies have revealed beneficial effects of EPO administration in various experimental models of ALI. Taken together, this treatment strategy is not a single mediator approach, but it rather provides protection by modulating multiple levels of early signaling pathways involved in apoptosis, inflammation, and peroxidation, potentially restoring overall homeostasis. Furthermore, EPO appears to confer vascular protection by promoting angiogenesis. However, only preliminary studies exist and more experimental and clinical studies are necessary to clarify the efficacy and potentially cytoprotective mechanisms of EPO action. In addition to the attempts to optimize the dose and timing of EPO administration, it would be of great value to minimize any potential toxicity, which is essential for EPO to fulfill its role as a potential candidate for the treatment of ALI in routine clinical practice. The present article reviews recent advances that have elucidated biological and biochemical activities of EPO that may be potentially applicable for ALI/ARDS management.
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Abstract
OBJECTIVE Besides its role in regulation of the complement and contact system, C1-esterase inhibitor has other immunomodulating effects that could prove beneficial in patients with acute inflammation such as during sepsis or after trauma. We examined the immunomodulating properties of C1-esterase inhibitor during human experimental endotoxemia, in which the innate immune system is activated in the absence of activation of the classic complement pathway. DESIGN Double-blind placebo-controlled study. SETTING Research intensive care unit of the Radboud University Nijmegen Medical Centre. SUBJECTS Twenty healthy volunteers. INTERVENTIONS Intravenous injection of 2 ng/kg Escherichia coli lipopolysaccharide. Thirty minutes thereafter (to prevent binding of lipopolysaccharide), C1-esterase inhibitor concentrate (100 U/kg, n = 10) or placebo (n = 10) was infused. MEASUREMENTS AND MAIN RESULTS Pro- and anti-inflammatory mediators, markers of endothelial and complement activation, hemodynamics, body temperature, and symptoms were measured. C1-esterase inhibitor reduced the release of proinflammatory cytokines as well as C-reactive protein (peak levels of: interleukin-6 1521 ± 209 vs. 932 ± 174 pg/mL [p = .04], tumor necrosis factor-α 1213 ± 187 vs. 827 ± 167 pg/mL [p = .10], monocyte chemotactic protein-1 6161 ± 1302 vs. 3373 ± 228 pg/mL [p = .03], interleukin-1β 34 ± 5 vs. 23 ± 2 pg/mL [p < .01], C-reactive protein 39 ± 4 vs. 29 ± 2 mg/L [p = .02]). In contrast, release of the anti-inflammatory cytokine interleukin-10 was increased by C1-esterase inhibitor (peak level 73 ± 11 vs. 121 ± 18 pg/mL, p = .02). The increase in interleukin-1 receptor antagonist tended to be smaller in the C1-esterase inhibitor group, but this effect did not reach statistical significance (p = .07). Markers for endothelial activation were increased after lipopolysaccharide infusion, but no significant differences between groups were observed. The lipopolysaccharide-induced changes in heart rate, blood pressure, body temperature, and symptoms (all p < .001 over time) were not influenced by C1-esterase inhibitor. Complement fragment C4 was not increased after lipopolysaccharide challenge. CONCLUSIONS This study is the first to demonstrate that C1-esterase inhibitor exerts anti-inflammatory effects in the absence of classic complement activation in humans.
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Krstić SN, Alempijević T, Popović N, Jovanović D, Mihailović V, Sijacki A. [Blood replacement in severely injured patients]. ACTA CHIRURGICA IUGOSLAVICA 2010; 57:107-113. [PMID: 20681210 DOI: 10.2298/aci1001110k] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Haemorrhage remains a leading cause of early death in injured and application of concentrated RBC transfusion in the treatment of multiple injuries is the basis and potential component of saving lives. The aim of this study was to analyze the received amount reimbursed blood in patients with severe trauma, depending on the outcome, severity and mechanism of injury. Collected data on gender, age and age as the mechanism of injury, amount of blood recovered intraoperatively and during the first six days of hospitalization, which were analyzed according to outcome of treatment, ISS, AIS, and APACHE II score. Results showed that patients with lethal outcome received a larger amount of blood, there is a statistically significant correlation with ISS and AIS score for extremity injuries, and that larger amount of blood received patients injured in the traffic accidents, as pedestrians and motorcycle riders/bike, and there is no correlation with APACHE II score. Based on the importance of this topic for further research are necessary in this area in order to more accurately define indications and dosage and method of reimbursement of blood in patient with severe trauma.
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Affiliation(s)
- S N Krstić
- Urgentni centar, Klinika za urgentnu abdominalnu hirurgiju, Klinicki Centar Srbije, Beograd
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Bao Z, Ye Q, Gong W, Xiang Y, Wan H. Humanized monoclonal antibody against the chemokine CXCL-8 (IL-8) effectively prevents acute lung injury. Int Immunopharmacol 2009; 10:259-63. [PMID: 19909826 DOI: 10.1016/j.intimp.2009.11.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2009] [Revised: 10/19/2009] [Accepted: 11/05/2009] [Indexed: 12/18/2022]
Abstract
As one of the most important endogenous chemotactic factors for neutrophils, the chemokine CXCL8 (IL-8) is involved in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by massive neutrophil infiltration in the lung. Since neutralization of CXCL8 with polyclonal antibody has been shown to reduce the severity of ALI/ARDS in animal models, we explored the potential of humanized anti-CXCL8 antibody as a preventive or therapeutic agent for ALI. We used a 'two-hit' protocol to induce ALI in rabbits that showed extensive edema in the alveolar lumina, marked infiltration of neutrophils in the lung tissue, fibrin deposition in alveolar space, and destruction of pulmonary architecture, culminating in severe hypoxemia. Concomitant challenge with endotoxin after priming with oleic acid (OA) induced a marked elevation of CXCL8 level in bronchoalveolar lavage fluid. Treatment of the rabbits with a humanized anti-CXCL8 antibody prevented neutrophil infiltration in the lung in association with alleviated ALI syndrome. Our results indicate a promising future for utilization of humanized anti-CXCL8 antibody in the prevention and treatment of ALI and ARDS in human.
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Affiliation(s)
- ZhiYao Bao
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
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Mabley JG, Pacher P, Murthy KGK, Williams W, Southan GJ, Salzman AL, Szabo C. The novel inosine analogue INO-2002 exerts an anti-inflammatory effect in a murine model of acute lung injury. Shock 2009; 32:258-62. [PMID: 19174745 PMCID: PMC2756476 DOI: 10.1097/shk.0b013e31819c3414] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Endogenous purines, including inosine, have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for these effects has been shown to be between 200 and 600 mg kg(-1) because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic resistant purine analog, INO-2002, exerts anti-inflammatory effects in an animal model of acute respiratory distress syndrome. Mice challenged with intratracheal LPS (50 microg) were treated with INO-2002 (30 or 100 mg kg(-1), i.p.) in divided doses at either 1 and 12 h or at 5 and 16 h. After 24 h, bronchoalveolar lavage fluid was obtained to measure leukocyte infiltration by myeloperoxidase levels, lung edema by protein levels, and proinflammatory chemokine (macrophage inflammatory protein 1alpha) and cytokine (TNF-alpha, IL-1, and IL-6) levels. INO-2002 (30 and 100 mg kg(-1)) reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by bronchoalveolar lavage fluid reduction in levels of myeloperoxidase and protein. INO-2002 also downregulated expression of the proinflammatory mediators macrophage inflammatory protein 1alpha, TNF-alpha, IL-1, and IL-6. Delaying the start of treatment by 5 h after LPS administration affected the potency of INO-2002 protective effects, with 100 but not 30 mg kg(-1) having anti-inflammatory effects. The inosine analog INO-2002 largely suppressed LPS-induced inflammation in vivo at doses lower than those needed for the naturally occurring purine inosine. These data support the proposal that purine analogs, resistant to metabolic breakdown, may represent a useful addition to the therapy of acute respiratory distress syndrome.
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Affiliation(s)
- Jon G Mabley
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK.
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Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med 2009; 10:387-92. [PMID: 19325510 DOI: 10.1097/pcc.0b013e3181a1ae08] [Citation(s) in RCA: 203] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In an effort to attain earlier diagnoses in children with hemophagocytic lymphohistiocytosis (HLH), the International Histiocyte Society has now broadened their diagnostic criteria to no longer differentiate primary (HLH) and secondary hemophagocytic lymphohistiocytosis (SHLH). Five of the following eight diagnostic criteria needed to be met: 1) fever, 2) cytopenia of two lines, 3) hypertriglyceridemia and/or hypofibrinogenemia, 4) hyperferritinemia (>500 microg/L), 5) hemophagocytosis, 6) elevated soluble interleukin-2 receptor (CD25), 7) decreased natural killer-cell activity, and 8) splenomegaly can also commonly be found in patients with sepsis, systemic inflammatory response syndrome (SIRS), multiorgan dysfunction syndrome (MODS), and macrophage activation syndrome (MAS). Nevertheless, the therapeutic options for these are radically different. Chemotherapy and bone marrow transplant have been used for treatment of HLH/SHLH, whereas antibiotics and supportive treatment are used in severe sepsis/SIRS and MODS. MAS is treated with limited immune suppression. Outcomes are also different, SHLH has a mortality rate around 50%, whereas pediatric septic shock and MODS have a mortality of 10.3% and 18%, respectively, and severe sepsis in previously healthy children has a mortality rate of 2%. MAS has a mortality rate between 8% and 22%. Because SHLH and severe sepsis/SIRS/MODS/MAS share clinical and laboratory inflammatory phenotypes, we recommend extreme caution when considering applying HLH therapies to children with sepsis/SIRS/MODS/MAS. HLH therapies are clearly warranted for children with HLH; however, a quantitative functional estimate of cytotoxic lymphocyte function may be a more precise approach to define the overlap of these conditions, better identify these processes, and develop novel therapeutic protocols that may lead to improved treatments and outcomes.
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Abstract
PURPOSE OF REVIEW Multiple organ failure is the main cause of late morbidity and mortality after severe injury. This disease state is driven by a dysfunctional immune system. Prediction of multiple organ failure on the basis of clinical parameters appears to be insufficient. A better understanding of immunological pathogenesis underlying multiple organ failure may lead to better prediction and innovation in treatment strategy in order to increase the survival of trauma patients. RECENT FINDINGS Immune monitoring has increased the knowledge of the pathogenesis of multiple organ failure, but many mechanisms underlying its cause and development remain to be elucidated. Consequently, adequate predictive markers for diagnosis and monitoring still need to be developed. SUMMARY General markers of inflammation including cytokines are correlated with posttraumatic complications with a low sensitivity and specificity and are, therefore, of little use as prognostic markers. Current findings regarding the functionality of immune cells are promising and might be of prognostic value in the near future.
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Gong MN. Myosin light chain kinase gene and acute lung injury in trauma and sepsis: opposite effects but confirmatory. Crit Care Med 2008; 36:2943-5. [PMID: 18812803 PMCID: PMC2703460 DOI: 10.1097/ccm.0b013e31818723b4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Flores C, Ma SF, Maresso K, Wade MS, Villar J, Garcia JGN. IL6 gene-wide haplotype is associated with susceptibility to acute lung injury. Transl Res 2008; 152:11-7. [PMID: 18593632 DOI: 10.1016/j.trsl.2008.05.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Revised: 05/23/2008] [Accepted: 05/24/2008] [Indexed: 01/31/2023]
Abstract
Experimental and clinical studies support the key role of interleukin 6 (IL-6), a potent proinflammatory cytokine, in the development of acute lung injury (ALI). Plasma IL-6 levels are influenced mainly by genetic determinants, and a -174G/C polymorphism of the gene has been recently associated with susceptibility to ALI. Here we aimed to validate the association of the IL6 gene with ALI in a case-control sample from Spain. DNA was isolated from 67 consecutive patients who fulfilled international criteria for severe sepsis and for ALI and 96 population-based controls drawn from the general population. Genotypes of the -174G/C polymorphism along with other 14 tagging variants of the IL6 gene were evaluated. Twenty polymorphisms unlinked to IL6 gene were additionally compared between cases and controls to rule out population stratification. None of the individual single-nucleotide polymorphisms was significantly associated with susceptibility to ALI. However, we found that a common haplotype from -1363 to +4835 from the transcription start site, and spanning the gene, conferred risk for susceptibility to ALI (odds ratio, 2.73; 95% confidence interval, 1.39-5.37; P = 0.003). Adjustment for relevant covariates did not modify this result. These data support the association of the IL6 gene with ALI susceptibility and illustrate the value of haplotype analysis as a robust approach for evaluating IL6 gene effects in association studies.
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Affiliation(s)
- Carlos Flores
- Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Ill 60637, USA
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Kallio R, Aalto H, Takala A, Ohtonen P, Collan J, Siitonen S, Joensuu H, Syrjala H, Repo H. Expression of CD11b/CD18 adhesion molecules on circulating phagocytes-a novel aid to diagnose infection in patients with cancer. Support Care Cancer 2008; 16:1389-96. [PMID: 18414903 DOI: 10.1007/s00520-008-0440-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2008] [Accepted: 03/06/2008] [Indexed: 11/30/2022]
Abstract
GOALS OF WORK No blood marker available to date is useful for distinguishing infection-related from neoplasm-related fever. We evaluated the expression of the peripheral blood phagocyte CD11b/CD18 adhesion molecule complex for this purpose. MATERIALS AND METHODS Neutrophil and monocyte CD11b/CD18 expression was assessed in two cohorts of patients with advanced solid cancer (n = 120) and in healthy controls (n = 63). The cancer series included 89 patients with verified infection, 23 without infection, and eight with neoplastic fever. CD11b/CD18 expression was measured using flow cytometry, and serum C-reactive protein (CRP) concentration was determined with immunoturbidimetric assay. RESULTS Cancer patients with infection had higher blood neutrophil and monocyte CD11b/CD18 expression levels than patients with neoplastic fever, those with advanced cancer without infection, or healthy controls (p < 0.01 for all analyses). High CD11b/CD18 values were measured exclusively in individuals diagnosed with infection. Receiver-operating characteristic area under the curve (AUC) for neutrophil and monocyte CD11b/CD18 expression for the discrimination of infection from neoplastic fever was 0.80 (95% CI, 0.70 to 0.88), which was superior (p = 0.039 and p = 0.049, respectively) to serum CRP on admission (AUC 0.51, 0.40 to 0.62). CONCLUSIONS Peripheral blood phagocytic cell CD11b/CD18 expression is useful for making a differential diagnosis between infection and neoplasm-related fever in cancer patients.
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Affiliation(s)
- R Kallio
- Department of Oncology and Radiotherapy, Oulu University Hospital, Box 22, 90029, Oulu, Finland.
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Tascilar O, Cakmak GK, Tekin IO, Emre AU, Ucan BH, Bahadir B, Acikgoz S, Irkorucu O, Karakaya K, Balbaloglu H, Kertis G, Ankarali H, Comert M. Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis. World J Gastroenterol 2008. [PMID: 18069756 DOI: 10.3748/wjg.13.6172] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of exogenous erythro-poietin (EPO) administration on acute lung injury (ALI) in an experimental model of sodium taurodeoxycholate- induced acute necrotizing pancreatitis (ANP). METHODS Forty-seven male Wistar albino rats were randomly divided into 7 groups: sham group (n = 5), 3 ANP groups (n = 7 each) and 3 EPO groups (n = 7 each). ANP was induced by retrograde infusion of 5% sodium taurodeoxycholate into the common bile duct. Rats in EPO groups received 1000 U/kg intramuscular EPO immediately after induction of ANP. Rats in ANP groups were given 1 mL normal saline instead. All animals were sacrificed at postoperative 24 h, 48 h and 72 h. Serum amilase, IL-2, IL-6 and lung tissue malondialdehyde (MDA) were measured. Pleural effusion volume and lung/body weight (LW/BW) ratios were calculated. Tissue levels of TNF-alpha, IL-2 and IL-6 were screened immunohistochemically. Additionally, ox-LDL accumulation was assessed with immune-fluorescent staining. Histopathological alterations in the lungs were also scored. RESULTS The mean pleural effusion volume, calculated LW/BW ratio, serum IL-6 and lung tissue MDA levels were significantly lower in EPO groups than in ANP groups. No statistically significant difference was observed in either serum or tissue values of IL-2 among the groups. The level of tumor necrosis factor-alpha (TNF-alpha) and IL-6 and accumulation of ox-LDL were evident in the lung tissues of ANP groups when compared to EPO groups, particularly at 72 h. Histopathological evaluation confirmed the improvement in lung injury parameters after exogenous EPO administration, particularly at 48 h and 72 h. CONCLUSION EPO administration leads to a significant decrease in ALI parameters by inhibiting polymorphonuclear leukocyte (PMNL) accumulation, decreasing the levels of proinflammatory cytokines in circulation, preserving microvascular endothelial cell integrity and reducing oxidative stress-associated lipid peroxidation and therefore, can be regarded as a cytoprotective agent in ANP-induced ALI.
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Affiliation(s)
- Oge Tascilar
- Department of Surgery, School of Medicine, Zonguldak Karaelmas Universitesi, Arastirma ve Uygulama Hastanesi Bashekimligi, Kozlu-Zonguldak 67600, Turkey
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Bhatia M, Sidhapuriwala JN, Sparatore A, Moore PK. Treatment with H2S-releasing diclofenac protects mice against acute pancreatitis-associated lung injury. Shock 2008; 29:84-88. [PMID: 17621252 DOI: 10.1097/shk.0b013e31806ec26] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Hydrogen sulfide (H(2)S) is a naturally occurring gas that has been shown to be a potent vasodilator. Diclofenac is a nonsteroidal anti-inflammatory drug and has been shown to have anti-inflammatory, analgesic, and antipyretic activity. ACS15 is an H(2)S-releasing derivative of diclofenac. Little is known about its effectiveness as an anti-inflammatory drug. In this report, we describe the effect of diclofenac and its H(2)S-releasing derivative on acute pancreatitis and associated lung injury in the mouse. Acute pancreatitis was induced in mice by hourly i.p. injections of cerulein. Diclofenac and ACS15 were administered either 1 hour before or 1 hour after starting cerulein injections, and the severity of acute pancreatitis and associated lung injury was assessed. The severity of acute pancreatitis was determined by hyperamylasemia, neutrophil sequestration in the pancreas (pancreatic myeloperoxidase activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. The severity of acute pancreatitis-associated lung injury was assessed by neutrophil sequestration in the lungs (lung myeloperoxidase activity) and by histological examination of lung sections. ACS15, given prophylactically and therapeutically, significantly reduced lung inflammation without having any significant effect on pancreatic injury. These results suggest the usefulness of H(2)S-releasing nonsteroidal anti-inflammatory drugs as potential treatments for pancreatitis-associated lung injury.
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Affiliation(s)
- Madhav Bhatia
- Department of Pharmacology and Cardiovascular Biology Research Group, National University of Singapore.
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47
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Tascilar O, Cakmak GK, Tekin IO, Emre AU, Ucan BH, Bahadir B, Acikgoz S, Irkorucu O, Karakaya K, Balbaloglu H, Kertis G, Ankarali H, Comert M. Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis. World J Gastroenterol 2007; 13:6172-82. [PMID: 18069756 PMCID: PMC4171226 DOI: 10.3748/wjg.v13.i46.6172] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of exogenous erythro-poietin (EPO) administration on acute lung injury (ALI) in an experimental model of sodium taurodeoxycholate-induced acute necrotizing pancreatitis (ANP).
METHODS: Forty-seven male Wistar albino rats were randomly divided into 7 groups: sham group (n = 5), 3 ANP groups (n = 7 each) and 3 EPO groups (n = 7 each). ANP was induced by retrograde infusion of 5% sodium taurodeoxycholate into the common bile duct. Rats in EPO groups received 1000 U/kg intramuscular EPO immediately after induction of ANP. Rats in ANP groups were given 1 mL normal saline instead. All animals were sacrificed at postoperative 24 h, 48 h and 72 h. Serum amilase, IL-2, IL-6 and lung tissue malondialdehyde (MDA) were measured. Pleural effusion volume and lung/body weight (LW/BW) ratios were calculated. Tissue levels of TNF-α, IL-2 and IL-6 were screened immunohistochemically. Additionally, ox-LDL accumulation was assessed with immune-fluorescent staining. Histopathological alterations in the lungs were also scored.
RESULTS: The mean pleural effusion volume, calculated LW/BW ratio, serum IL-6 and lung tissue MDA levels were significantly lower in EPO groups than in ANP groups. No statistically significant difference was observed in either serum or tissue values of IL-2 among the groups. The level of tumor necrosis factor-α (TNF-α) and IL-6 and accumulation of ox-LDL were evident in the lung tissues of ANP groups when compared to EPO groups, particularly at 72 h. Histopathological evaluation confirmed the improvement in lung injury parameters after exogenous EPO administration, particularly at 48 h and 72 h.
CONCLUSION: EPO administration leads to a significant decrease in ALI parameters by inhibiting polymorphonuclear leukocyte (PMNL) accumulation, decreasing the levels of proinflammatory cytokines in circulation, preserving microvascular endothelial cell integrity and reducing oxidative stress-associated lipid peroxidation and therefore, can be regarded as a cytoprotective agent in ANP-induced ALI.
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Nonas SA, Moreno-Vinasco L, Vinasco LM, Ma SF, Jacobson JR, Desai AA, Dudek SM, Flores C, Hassoun PM, Sam L, Ye SQ, Moitra J, Barnard J, Grigoryev DN, Lussier YA, Garcia JGN. Use of consomic rats for genomic insights into ventilator-associated lung injury. Am J Physiol Lung Cell Mol Physiol 2007; 293:L292-302. [PMID: 17468131 PMCID: PMC3616407 DOI: 10.1152/ajplung.00481.2006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Increasing evidence supports the contribution of genetic influences on susceptibility/severity in acute lung injury (ALI), a devastating syndrome requiring mechanical ventilation with subsequent risk for ventilator-associated lung injury (VALI). To identify VALI candidate genes, we determined that Brown Norway (BN) and Dahl salt-sensitive (SS) rat strains were differentially sensitive to VALI (tidal volume of 20 ml/kg, 85 breaths/min, 2 h) defined by bronchoalveolar lavage (BAL) protein and leukocytes. We next exploited differential sensitivities and phenotyped both the VALI-sensitive BN and the VALI-resistant SS rat strains by expression profiling coupled to a bioinformatic-intense candidate gene approach (Significance Analysis of Microarrays, i.e., SAM). We identified 106 differentially expressed VALI genes representing gene ontologies such as "transcription" and "chemotaxis/cell motility." We mapped the chromosomal location of the differentially expressed probe sets and selected consomic SS rats with single BN introgressions of chromosomes 2, 13, and 16 (based on the highest density of probe sets) while also choosing chromosome 20 (low probe sets density). VALI exposure of consomic rats with introgressions of BN chromosomes 13 and 16 resulted in significant increases in both BAL cells and protein (compared to parental SS strain), whereas introgression of BN chromosome 2 displayed a large increase only in BAL protein. Introgression of BN chromosome 20 had a minimal effect. These results suggest that genes residing on BN chromosomes 2, 13, and 16 confer increased sensitivity to high tidal volume ventilation. We speculate that the consomic-microarray-SAM approach is a time- and resource-efficient tool for the genetic dissection of complex diseases including VALI.
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Affiliation(s)
- Stephanie A Nonas
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Yeh CC, Lin CC, Wang SD, Hung CM, Yeh MH, Liu CJ, Kao ST. Protective and immunomodulatory effect of Gingyo-san in a murine model of acute lung inflammation. JOURNAL OF ETHNOPHARMACOLOGY 2007; 111:418-26. [PMID: 17276022 DOI: 10.1016/j.jep.2006.12.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2006] [Revised: 11/29/2006] [Accepted: 12/08/2006] [Indexed: 05/13/2023]
Abstract
To investigate the effects of Gingyo-san (GGS), the traditional Chinese medicinal formula, on the acute lung inflammation induced by LPS in vivo, mice were challenged with intratracheal LPS before treatment with GGS or vehicle. In lung morphology, GGS reduced the infiltration of activated polymorphonuclear neutrophils in the airways, decreased pulmonary edema, reduced nitrosative stress, and improved lung morphology. ELISA or RT-PCR detected the expression of cytokines in BALF and lung tissue. The mechanism of these benefits by treatment with GGS including attenuating expression TNFalpha, IL-1 beta, IL-6, KC, MCP-1, MIP-2, iNOS, and activation of nuclear factor (NF-kappaB and AP-1) in BALF and lung tissue. Particularly, GGS also enhanced the anti-inflammatory cytokine (IL-10) and limited the acute lung inflammation. Therefore, its protection activity against LPS-induced lung inflammatory mediators release might be beneficial in the treatment of endotoxin-associated inflammation.
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Affiliation(s)
- Chia-Chou Yeh
- Institute of Chinese Medical Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan
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Huber-Wagner S, Qvick M, Mussack T, Euler E, Kay MV, Mutschler W, Kanz KG. Massive blood transfusion and outcome in 1062 polytrauma patients: a prospective study based on the Trauma Registry of the German Trauma Society. Vox Sang 2007; 92:69-78. [PMID: 17181593 DOI: 10.1111/j.1423-0410.2006.00858.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND OBJECTIVES About 15% of polytrauma patients receive massive blood transfusion (MBT) defined as > or = 10 units of packed red blood cells (PRBC). In general, the prognosis of trauma patients receiving MBT is considered to be poor. The purpose of this study was to investigate the impact of MBT on the outcome of polytrauma patients. MATERIALS AND METHODS Records of 10 997 patients in the Trauma Registry of the German Trauma Society were analysed. Transfusion data were available from 8182 severe trauma patients with a mean injury severity score of 24.5 and, of these 8182 patients, 1062 received > or = 10 units of PRBC. First, a logistic regression model for the predictors of mortality was performed. Second, incidences of organ failure and sepsis as well as survival rates were analysed. RESULTS The highest risk for mortality was age over 55 years (odds ratios [OR] 4.7; confidence intervals [CI 95%], 3.5-6.5) followed by Glasgow Coma Scale < or = 8 (OR 4.6; 3.4-6.1), MBT > or = 20 units of PRBC (OR 3.3; 2.1-5.4), thromboplastin time < 50% (OR 3.2; 2.2-4.4) and injury severity score > or = 24 (OR 2.9; 2.1-4.1). Transfusion of 10-19 PRBC was identified as the variable with the lowest risk for mortality (OR 1.5; 1.0-2.3). Risk of organ failure, sepsis and death correlated with increasing transfusion amount. For the MBT patients, the survival rate was 56.9% (CI 95%, 53.9-59.9%) compared to 85.2% (84.4-86.0%) of non-MBT patients (P < 0.001). In the MBT group with > 30 PRBC (mean 40.6 PRBC) 39.6% survived (31.7-47.5%). CONCLUSION Massive blood transfusion is one main prognostic factor for mortality in trauma. Although MBT is generally considered to be critical, every second trauma patient with MBT survived. A cut-off value for the number of PRBC could not be determined. Extended transfusion management even with high amounts of PRBC seems to be justified.
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Affiliation(s)
- S Huber-Wagner
- Munich University Hospital, Department of Trauma Surgery, Nussbaumstrasse 20, D-80336 Munich, Germany.
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