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1
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Chen Y, Zhao H, Cao S, Xie H, Huang J, Chen X, Cui Z. Molecular characterization of large yellow croaker (Larimichthys crocea) coagulation factor Ⅶ-like and its function on macrophage proliferation and polarization. FISH & SHELLFISH IMMUNOLOGY 2025; 158:110174. [PMID: 39914795 DOI: 10.1016/j.fsi.2025.110174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 01/20/2025] [Accepted: 02/02/2025] [Indexed: 02/11/2025]
Abstract
The coagulation system is a mechanism for wound healing after injury, but it also participates in host early immune defense. The coagulation factor Ⅶ (FⅦ) can initiate extrinsic pathway and play an important role in the coagulation process. However, studies of the immune function of FVII are scarce, especially in fish. In this study, we cloned and characterized an FⅦ-like gene from large yellow croaker (Larimichthys crocea) (LcFⅦL). The open reading frame of LcFⅦL consists of 1437 base pairs and encodes 478 amino acid residues. LcFⅦL contains conserved domains that are present in other vertebrate FⅦs or FⅦLs, including a prepropeptide, a gamma-carboxy glutamic acid domain, two epidermal growth factor-like domains, and a serine protease domain. LcFⅦL was highly expressed in the liver and brain, but its expression was low in the other tested tissues. At the cellular level, LcFⅦL was highly expressed in macrophages, and its expression was induced by exposure to Pseudomonas plecoglossicida. We produced the recombinant LcFⅦL light chain (rLcFⅦL-LC), and found that it had obvious antibacterial effects against Gram-positive bacteria but low against Gram-negative bacteria. The rLcFⅦL-LC promoted the proliferation of macrophages. It also significantly induced the expression of proinflammatory factor (IL-1β and IL-6) and increased reactive oxygen species activity in large yellow croaker macrophages, while inhibited the expression of anti-inflammatory factor (TGF-β), suggesting that rLcFⅦL-LC may promote polarization of macrophages towards the M1 type. Taken together, these findings provide insight into the function of fish FⅦ, and advance our understanding of the role of the coagulation system in host defense.
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Affiliation(s)
- Yueming Chen
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Han Zhao
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Shuangshuang Cao
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Hongjun Xie
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Jieyu Huang
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Xinhua Chen
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Fuzhou Institute of Oceanography, Fuzhou, 350108, China.
| | - Zhengwei Cui
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
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2
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Sokou R, Gounari EA, Tsante KA, Konstantinidi A, Lampridou M, Theodoraki M, Kriebardis AG, Fortis SP, Iacovidou N, Tsantes AG. Thromboelastometry-Based Profiling of Haemostatic Alterations in Neonatal Sepsis by Causative Pathogens. Antibiotics (Basel) 2025; 14:101. [PMID: 39858386 PMCID: PMC11762746 DOI: 10.3390/antibiotics14010101] [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: 11/29/2024] [Revised: 01/06/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Neonatal sepsis is a serious condition with high mortality, especially in premature and low-birth-weight neonates. This study aims to examine whether the haemostatic profile of neonates with sepsis defers depending on the type of bacteria (Gram-positive or Gram-negative), by using the method of Rotational Thromboelastometry (ROTEM). Methods: This single-centre prospective cohort study was conducted on 128 neonates with sepsis, including 95 cases caused by Gram-negative pathogens and 33 cases caused by Gram-positive bacteria. All participants were hospitalised in the Neonatal Intensive Care Unit (NICU). ROTEM parameters were compared between neonates with Gram-positive and Gram-negative infections. Results: The ROTEM parameters were found to be significantly different between neonates suffering from Gram-positive versus Gram-negative infections, with Gram-positive pathogens associated with an increased clotting potential compared to Gram-negative pathogens. This is reflected in the higher ROTEM values such as A10, α-angle, and MCF in the EXTEM and INTEM assays. Multivariant analysis showed that Gram-positive infections were linked to increased clot thickness at 10 min (coefficient: 8.9, CI: 2.8-15.0, p = 0.004), higher maximum clot stability (coefficient: 10.4, CI: 4.3-16.6, p = 0.001), and a bigger α-angle (coefficient: 8.0, CI: 2.7-13.2, p = 0.003). Similar findings were observed in the INTEM assay parameters. Conclusions: Neonatal sepsis caused by Gram-positive bacteria leads to a hypercoagulable haemostatic state, whereas neonates with sepsis caused by Gram-negative bacteria exhibit a more hypocoagulable profile and a higher incidence of haemorrhagic episodes. These findings provide valuable insights into the haemostatic disorders associated with sepsis, and may aid in developing an individualised approach for the treatment of those disorders, dependent on and adapted for the specific type of causative organism.
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Affiliation(s)
- Rozeta Sokou
- Neonatal Intensive Care Unit, “Agios Panteleimon” General Hospital of Nikea, 18454 Piraeus, Greece; (A.K.); (M.L.); (M.T.)
- Neonatal Department, Aretaieio Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | | | - Konstantina A. Tsante
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece; (K.A.T.); (A.G.K.); (S.P.F.)
| | - Aikaterini Konstantinidi
- Neonatal Intensive Care Unit, “Agios Panteleimon” General Hospital of Nikea, 18454 Piraeus, Greece; (A.K.); (M.L.); (M.T.)
| | - Maria Lampridou
- Neonatal Intensive Care Unit, “Agios Panteleimon” General Hospital of Nikea, 18454 Piraeus, Greece; (A.K.); (M.L.); (M.T.)
| | - Martha Theodoraki
- Neonatal Intensive Care Unit, “Agios Panteleimon” General Hospital of Nikea, 18454 Piraeus, Greece; (A.K.); (M.L.); (M.T.)
| | - Anastasios G. Kriebardis
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece; (K.A.T.); (A.G.K.); (S.P.F.)
| | - Sotirios P. Fortis
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece; (K.A.T.); (A.G.K.); (S.P.F.)
| | - Nicoletta Iacovidou
- Neonatal Department, Aretaieio Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Andreas G. Tsantes
- Laboratory of Haematology and Blood Bank Unit, “Attikon” Hospital, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece;
- Microbiology Department, “Saint Savvas” Oncology Hospital, 11522 Athens, Greece
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3
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Satala D, Bednarek A, Kozik A, Rapala-Kozik M, Karkowska-Kuleta J. The Recruitment and Activation of Plasminogen by Bacteria-The Involvement in Chronic Infection Development. Int J Mol Sci 2023; 24:10436. [PMID: 37445613 DOI: 10.3390/ijms241310436] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
The development of infections caused by pathogenic bacteria is largely related to the specific properties of the bacterial cell surface and extracellular hydrolytic activity. Furthermore, a significant role of hijacking of host proteolytic cascades by pathogens during invasion should not be disregarded during consideration of the mechanisms of bacterial virulence. This is the key factor for the pathogen evasion of the host immune response, tissue damage, and pathogen invasiveness at secondary infection sites after initial penetration through tissue barriers. In this review, the mechanisms of bacterial impact on host plasminogen-the precursor of the important plasma serine proteinase, plasmin-are characterized, principally focusing on cell surface exposition of various proteins, responsible for binding of this host (pro)enzyme and its activators or inhibitors, as well as the fibrinolytic system activation tactics exploited by different bacterial species, not only pathogenic, but also selected harmless residents of the human microbiome. Additionally, the involvement of bacterial factors that modulate the process of plasminogen activation and fibrinolysis during periodontitis is also described, providing a remarkable example of a dual use of this host system in the development of chronic diseases.
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Affiliation(s)
- Dorota Satala
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Aneta Bednarek
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-387 Kraków, Poland
| | - Andrzej Kozik
- Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Maria Rapala-Kozik
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
| | - Justyna Karkowska-Kuleta
- Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland
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Bass GA, Dzierba AL, Taylor B, Lane-Fall M, Kaplan LJ. Tertiary peritonitis: considerations for complex team-based care. Eur J Trauma Emerg Surg 2022; 48:811-825. [PMID: 34302503 PMCID: PMC8308068 DOI: 10.1007/s00068-021-01750-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/18/2021] [Indexed: 12/14/2022]
Abstract
Peritonitis, as a major consequence of hollow visceral perforation, anastomotic disruption, ischemic necrosis, or other injuries of the gastrointestinal tract, often drives acute care in the emergency department, operating room, and the ICU. Chronic critical illness (CCI) represents a devastating challenge in modern surgical critical care where successful interventions have fostered a growing cohort of patients with prolonged dependence on mechanical ventilation and other organ supportive therapies who would previously have succumbed much earlier in the acute phase of critical illness. An important subset of CCI patients are those who have survived an emergency abdominal operation, but who subsequently require prolonged open abdomen management complicated by persistent peritoneal space infection or colonization, fistula formation, and gastrointestinal (GI) tract dysfunction; these patients are described as having tertiary peritonitis (TP).The organ dysfunction cascade in TP terminates in death in between 30 and 64% of patients. This narrative review describes key-but not all-elements in a framework for the coordinate multiprofessional team-based management of a patient with tertiary peritonitis to mitigate this risk of death and promote recovery. Given the prolonged critical illness course of this unique patient population, early and recurrent Palliative Care Medicine consultation helps establish goals of care, support adjustment to changes in life circumstance, and enable patient and family centered care.
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Affiliation(s)
- Gary Alan Bass
- Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine, University of Pennsylvania, 51 N. 39th Street, MOB 1, Suite 120, Philadelphia, PA 19104 USA
- Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, USA
- European Society of Trauma and Emergency Surgery, Visceral Trauma Section, Philadelphia, USA
| | - Amy L. Dzierba
- Department of Pharmacy, New York-Presbyterian Hospital, Columbia University Irving Medical Center, New York, NY USA
| | - Beth Taylor
- Department of Research for Patient Care Services, Barnes-Jewish Hospital, St. Louis, MO USA
| | - Meghan Lane-Fall
- Department of Anesthesia and Critical Care, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5 Dulles, Philadelphia, PA 19104 USA
| | - Lewis J. Kaplan
- Division of Traumatology, Surgical Critical Care and Emergency Surgery, Perelman School of Medicine, University of Pennsylvania, 51 N. 39th Street, MOB 1, Suite 120, Philadelphia, PA 19104 USA
- Surgical Services, Section of Surgical Critical Care, Corporal Michael J Crescenz VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104 USA
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Satta S, Lai A, Cavallero S, Williamson C, Chen J, Blázquez‐Medela AM, Roustaei M, Dillon BJ, Ashammakhi N, Carlo DD, Li Z, Sun R, Hsiai TK. Rapid Detection and Inhibition of SARS-CoV-2-Spike Mutation-Mediated Microthrombosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2103266. [PMID: 34687279 PMCID: PMC8646611 DOI: 10.1002/advs.202103266] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/21/2021] [Indexed: 05/26/2023]
Abstract
Activation of endothelial cells following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be the primary driver for the increasingly recognized thrombotic complications in coronavirus disease 2019 patients, potentially due to the SARS-CoV-2 Spike protein binding to the human angiotensin-converting enzyme 2 (hACE2). Vaccination therapies use the same Spike sequence or protein to boost host immune response as a protective mechanism against SARS-CoV-2 infection. As a result, cases of thrombotic events are reported following vaccination. Although vaccines are generally considered safe, due to genetic heterogeneity, age, or the presence of comorbidities in the population worldwide, the prediction of severe adverse outcome in patients remains a challenge. To elucidate Spike proteins underlying patient-specific-vascular thrombosis, the human microcirculation environment is recapitulated using a novel microfluidic platform coated with human endothelial cells and exposed to patient specific whole blood. Here, the blood coagulation effect is tested after exposure to Spike protein in nanoparticles and Spike variant D614G in viral vectors and the results are corroborated using live SARS-CoV-2. Of note, two potential strategies are also examined to reduce blood clot formation, by using nanoliposome-hACE2 and anti-Interleukin (IL) 6 antibodies.
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Affiliation(s)
- Sandro Satta
- Division of CardiologyDepartment of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
| | - Angela Lai
- Division of CardiologyDepartment of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
| | - Susana Cavallero
- Division of CardiologyDepartment of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
- Department of MedicineVeterans Affairs Greater Los Angeles Healthcare SystemLos AngelesCA90073USA
| | - Cayden Williamson
- Department of BioengineeringHenry Samueli School of Engineering & Applied ScienceUniversity of CaliforniaLos AngelesCA90095USA
| | - Justin Chen
- Department of BioengineeringHenry Samueli School of Engineering & Applied ScienceUniversity of CaliforniaLos AngelesCA90095USA
| | - Ana M. Blázquez‐Medela
- Division of CardiologyDepartment of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
| | - Mehrdad Roustaei
- Department of BioengineeringHenry Samueli School of Engineering & Applied ScienceUniversity of CaliforniaLos AngelesCA90095USA
| | - Barbara J. Dillon
- Division of CardiologyDepartment of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
| | - Nureddin Ashammakhi
- Department of BioengineeringHenry Samueli School of Engineering & Applied ScienceUniversity of CaliforniaLos AngelesCA90095USA
| | - Dino Di Carlo
- Department of BioengineeringHenry Samueli School of Engineering & Applied ScienceUniversity of CaliforniaLos AngelesCA90095USA
| | - Zhaoping Li
- Department of MedicineVeterans Affairs Greater Los Angeles Healthcare SystemLos AngelesCA90073USA
- Division of Clinical NutritionDepartment of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
| | - Ren Sun
- Department of Molecular and Medical PharmacologyDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
- School of Biomedical SciencesLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
| | - Tzung K. Hsiai
- Division of CardiologyDepartment of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA90095USA
- Department of MedicineVeterans Affairs Greater Los Angeles Healthcare SystemLos AngelesCA90073USA
- Department of BioengineeringHenry Samueli School of Engineering & Applied ScienceUniversity of CaliforniaLos AngelesCA90095USA
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6
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Kearney KJ, Ariëns RAS, Macrae FL. The Role of Fibrin(ogen) in Wound Healing and Infection Control. Semin Thromb Hemost 2021; 48:174-187. [PMID: 34428799 DOI: 10.1055/s-0041-1732467] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Fibrinogen, one of the most abundant plasma proteins playing a key role in hemostasis, is an important modulator of wound healing and host defense against microbes. In the current review, we address the role of fibrin(ogen) throughout the process of wound healing and subsequent tissue repair. Initially fibrin(ogen) acts as a provisional matrix supporting incoming leukocytes and acting as reservoir for growth factors. It later goes on to support re-epithelialization, angiogenesis, and fibroplasia. Importantly, removal of fibrin(ogen) from the wound is essential for wound healing to progress. We also discuss how fibrin(ogen) functions through several mechanisms to protect the host against bacterial infection by providing a physical barrier, entrapment of bacteria in fibrin(ogen) networks, and by directing immune cell function. The central role of fibrin(ogen) in defense against bacterial infection has made it a target of bacterial proteins, evolved to interact with fibrin(ogen) to manipulate clot formation and degradation for the purpose of promoting microbial virulence and survival. Further understanding of the dual roles of fibrin(ogen) in wound healing and infection could provide novel means of therapy to improve recovery from surgical or chronic wounds and help to prevent infection from highly virulent bacterial strains, including those resistant to antibiotics.
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Affiliation(s)
- Katherine J Kearney
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
| | - Robert A S Ariëns
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.,Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Fraser L Macrae
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
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7
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Erenberg M, Rotem R, Segal D, Yohay Z, Idan I, Yohay D, Weintraub AY. Adhesion barriers and topical hemostatic agents are risk factors for post-cesarean section infections. Surgery 2021; 170:1120-1124. [PMID: 33933281 DOI: 10.1016/j.surg.2021.03.048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Cesarean sections are the most common surgery worldwide, and post-cesarean section infections and hemorrhage are a major cause for morbidity and mortality. In recent years, many surgeons use adhesion barriers as well as hemostatic agents during primary and repeated cesarean section. The data regarding the safety of these agents is relatively limited. The objective of this study was to investigate whether the use of adhesion barriers and topical hemostatic agents pose a risk for post-cesarean section infections. METHOD A case-control study composed of women who were admitted to the Soroka University Medical Center between the years 2012 and 2016 was conducted. The study group was composed of women admitted owing to post-cesarean section infections (cases) and those who underwent cesarean sections without post-cesarean section infection (control subjects). Matching was done according to date and surgery setting (elective versus emergency). A univariate analysis was followed by a multiple regression model in order to examine the association between adhesion barriers/hemostatic agents and post-cesarean section infections. RESULTS During the study period, 113 patients developed postoperative infection (cases); 71.7% were diagnosed with surgical site infection, 7.1% with endometritis, and 21.2% with other infections. These were compared with 226 control subjects. In the univariate analysis, the use of adhesion barriers/hemostatic agents were found to be associated with post-cesarean section infection. Using a multivariable analysis controlling for previous cesarean section, skin closer technique, preterm delivery, and duration of surgery >60 minutes, the use of adhesion barriers as well as hemostatic agents was found to be independently associated with post-cesarean section infection (adjusted odds ratio = 2.11, 95% confidence interval = 1.17-3.84; adjusted odds ratio = 2.29, 95% confidence interval = 1.37-3.8, respectively) CONCLUSION: Adhesion barriers and hemostatic agents were found to be independently associated with post-cesarean section infections. Further larger studies are needed to reinforce our findings. The use of these materials should be carefully considered, and their cost-effectiveness re-examined.
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Affiliation(s)
- Miriam Erenberg
- Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
| | - Reut Rotem
- Obstetric and Gynecology, Shaare Zedek Medical Center, affiliated with the Hebrew University Medical School of Jerusalem, Israel
| | - David Segal
- Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Zehava Yohay
- Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Inbal Idan
- Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - David Yohay
- Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Adi Y Weintraub
- Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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8
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Keshava S, Magisetty J, Tucker TA, Kujur W, Mulik S, Esmon CT, Idell S, Rao LVM, Pendurthi UR. Endothelial Cell Protein C Receptor Deficiency Attenuates Streptococcus pneumoniae-induced Pleural Fibrosis. Am J Respir Cell Mol Biol 2021; 64:477-491. [PMID: 33600743 PMCID: PMC8008801 DOI: 10.1165/rcmb.2020-0328oc] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 01/19/2021] [Indexed: 12/15/2022] Open
Abstract
Streptococcus pneumoniae is the leading cause of hospital community-acquired pneumonia. Patients with pneumococcal pneumonia may develop complicated parapneumonic effusions or empyema that can lead to pleural organization and subsequent fibrosis. The pathogenesis of pleural organization and scarification involves complex interactions between the components of the immune system, coagulation, and fibrinolysis. EPCR (endothelial protein C receptor) is a critical component of the protein C anticoagulant pathway. The present study was performed to evaluate the role of EPCR in the pathogenesis of S. pneumoniae infection-induced pleural thickening and fibrosis. Our studies show that the pleural mesothelium expresses EPCR. Intrapleural instillation of S. pneumoniae impairs lung compliance and lung volume in wild-type and EPCR-overexpressing mice but not in EPCR-deficient mice. Intrapleural S. pneumoniae infection induces pleural thickening in wild-type mice. Pleural thickening is more pronounced in EPCR-overexpressing mice, whereas it is reduced in EPCR-deficient mice. Markers of mesomesenchymal transition are increased in the visceral pleura of S. pneumoniae-infected wild-type and EPCR-overexpressing mice but not in EPCR-deficient mice. The lungs of wild-type and EPCR-overexpressing mice administered intrapleural S. pneumoniae showed increased infiltration of macrophages and neutrophils, which was significantly reduced in EPCR-deficient mice. An analysis of bacterial burden in the pleural lavage, the lungs, and blood revealed a significantly lower bacterial burden in EPCR-deficient mice compared with wild-type and EPCR-overexpressing mice. Overall, our data provide strong evidence that EPCR deficiency protects against S. pneumoniae infection-induced impairment of lung function and pleural remodeling.
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Affiliation(s)
| | | | | | - Weshely Kujur
- Department of Pulmonary Immunology, The University of Texas Health Science Center at Tyler, Tyler, Texas; and
| | - Sachin Mulik
- Department of Pulmonary Immunology, The University of Texas Health Science Center at Tyler, Tyler, Texas; and
| | - Charles T. Esmon
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
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9
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Gibson CR, Amirabadi A, Goman S, Armstrong NC, Langer JC, Amaral JG, Temple MJ, Parra D, John PR, Connolly BL. Use of Tissue Plasminogen Activator in Abdominal Abscesses in Children-A Single-Center Randomized Control Trial. Can Assoc Radiol J 2020; 72:577-584. [PMID: 32281404 DOI: 10.1177/0846537120914263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
PURPOSE To establish the efficacy of once-per-day intracavitary tissue plasminogen activator (tPA) in the treatment of pediatric intra-abdominal abscesses. METHODS A single-center prospective, double-blinded, randomized controlled trial of the use of intracavitary tPA in abdominal abscesses in children. Patients were randomized to either tPA-treatment or saline-treatment groups. Primary outcome was drainage catheter dwell (hours). Secondary outcomes were length of hospital stay, times to discharge, clinical and sonographic resolution, and adverse events (AEs). RESULTS Twenty-eight children were randomized to either group (n = 14 each). Demographics between groups were not significantly different (age P = .28; weight P = .40; gender P = .44). There were significantly more abscesses in the tPA-treated group (P = .03). Abscesses were secondary to perforated appendicitis (n = 25) or postappendectomy (n = 3). Thirty-four abscesses were drained, 4 aspirated, 3 neither drained/aspirated. There was no significant difference in number of drains (P = .14), drain size (P = .19), primary outcome (P = .077), or secondary outcomes found. No procedural or intervention drug-related AEs occurred. No patient in the saline-treated group required to be switched/treated with tPA. CONCLUSION No significant difference in the length of catheter dwell time, procedure time to discharge, or time to resolution was found. Intracavitary tPA was not associated with morbidity or mortality. The results neither support nor negate routine use of tPA in the drainage of intra-abdominal abscess in children. It is possible that a multicentre study with a larger number of patients may answer this question more definitively.
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Affiliation(s)
- Craig R Gibson
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,Perth Children's Hospital, Nedlands, Australia
| | - Afsaneh Amirabadi
- Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Simal Goman
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Nicholas C Armstrong
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,8808University of Limerick, Graduate Entry Medical School, Limerick, Ireland
| | - Jacob C Langer
- Division of General and Thoracic Surgery, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Surgery, University of Toronto, Ontario, Canada
| | - Joao G Amaral
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Medical Imaging, University of Toronto, Ontario, Canada
| | - Michael J Temple
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Medical Imaging, University of Toronto, Ontario, Canada
| | - Dimitri Parra
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Medical Imaging, University of Toronto, Ontario, Canada
| | - Philip R John
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Medical Imaging, University of Toronto, Ontario, Canada
| | - Bairbre L Connolly
- Image Guided Therapy, Diagnostic Imaging, 7979The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Medical Imaging, University of Toronto, Ontario, Canada
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10
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Kuang M, Peng Y, Tao X, Zhou Z, Mao H, Zhuge L, Sun Y, Zhang H. FGB and FGG derived from plasma exosomes as potential biomarkers to distinguish benign from malignant pulmonary nodules. Clin Exp Med 2019; 19:557-564. [PMID: 31576477 DOI: 10.1007/s10238-019-00581-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 09/21/2019] [Indexed: 12/11/2022]
Abstract
Previous proteomic analysis (label-free) of plasma exosomes revealed that the expression of FGG and FGB was significantly higher in the malignant pulmonary nodules group, compared to the benign pulmonary nodules group. The present study was performed to evaluate the role of plasma exosomal proteins FGB and FGG in the diagnosis of benign and malignant pulmonary nodules. We examined the expression levels of FGB and FGG in plasma exosomes from 63 patients before surgery. Postoperative pathological diagnosis confirmed that 43 cases were malignant and 20 cases were benign. The ROC curve was used to describe the sensitivity, specificity, area under the curve (AUC) of the biomarker and the corresponding 95% confidence interval. We confirmed that the expression levels of FGB and FGG were higher in the plasma exosomes of malignant group than in the benign group. The sensitivity and AUC of FGB combined with FGG detection to determine the nature of pulmonary nodules are superior to single FGB or FGG detection. FGB and FGG might represent novel and sensitive biomarker to distinguish benign from malignant pulmonary nodules.
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Affiliation(s)
- Muyu Kuang
- Huadong Hospital, Fudan University, Shanghai, China.,Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yizhou Peng
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaoting Tao
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zilang Zhou
- The First High School, Xintian County, Hunan, China
| | - Hengyu Mao
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lingdun Zhuge
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yihua Sun
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Huibiao Zhang
- Huadong Hospital, Fudan University, Shanghai, China.
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11
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Affiliation(s)
- Gisli Jenkins
- Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, UK
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12
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Koenigs A, Stahl J, Averhoff B, Göttig S, Wichelhaus TA, Wallich R, Zipfel PF, Kraiczy P. CipA of Acinetobacter baumannii Is a Novel Plasminogen Binding and Complement Inhibitory Protein. J Infect Dis 2015; 213:1388-99. [PMID: 26681776 DOI: 10.1093/infdis/jiv601] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 12/03/2015] [Indexed: 01/08/2023] Open
Abstract
Acinetobacter baumannii is an emerging opportunistic pathogen, responsible for up to 10% of gram-negative, nosocomial infections. The global increase of multidrug-resistant and pan-resistant Acinetobacter isolates presents clinicians with formidable challenges. To establish a persistent infection,A. baumannii must overcome the detrimental effects of complement as the first line of defense against invading microorganisms. However, the immune evasion principles underlying serum resistance inA. baumannii remain elusive. Here, we identified a novel plasminogen-binding protein, termed CipA. Bound plasminogen, upon conversion to active plasmin, degraded fibrinogen and complement C3b and contributed to serum resistance. Furthermore, CipA directly inhibited the alternative pathway of complement in vitro, irrespective of its ability to bind plasminogen. A CipA-deficient mutant was efficiently killed by human serum and showed a defect in the penetration of endothelial monolayers, demonstrating that CipA is a novel multifunctional protein that contributes to the pathogenesis ofA. baumannii.
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Affiliation(s)
- Arno Koenigs
- Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt
| | - Julia Stahl
- Department of Molecular Microbiology and Bioenergetics, Institute of Molecular Biosciences, Goethe University, Frankfurt
| | - Beate Averhoff
- Department of Molecular Microbiology and Bioenergetics, Institute of Molecular Biosciences, Goethe University, Frankfurt
| | - Stephan Göttig
- Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt
| | - Thomas A Wichelhaus
- Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt
| | | | - Peter F Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology Friedrich Schiller University, Jena, Germany
| | - Peter Kraiczy
- Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt
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13
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Loof TG, Deicke C, Medina E. The role of coagulation/fibrinolysis during Streptococcus pyogenes infection. Front Cell Infect Microbiol 2014; 4:128. [PMID: 25309880 PMCID: PMC4161043 DOI: 10.3389/fcimb.2014.00128] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 08/27/2014] [Indexed: 02/02/2023] Open
Abstract
The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis and is a host defense mechanism that protects the integrity of the vascular system after tissue injury. During bacterial infections, the coagulation system cooperates with the inflammatory system to eliminate the invading pathogens. However, pathogenic bacteria have frequently evolved mechanisms to exploit the hemostatic system components for their own benefit. Streptococcus pyogenes, also known as Group A Streptococcus, provides a remarkable example of the extraordinary capacity of pathogens to exploit the host hemostatic system to support microbial survival and dissemination. The coagulation cascade comprises the contact system (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), both leading to fibrin formation. During the early phase of S. pyogenes infection, the activation of the contact system eventually leads to bacterial entrapment within a fibrin clot, where S. pyogenes is immobilized and killed. However, entrapped S. pyogenes can circumvent the antimicrobial effect of the clot by sequestering host plasminogen on the bacterial cell surface that, after conversion into its active proteolytic form, plasmin, degrades the fibrin network and facilitates the liberation of S. pyogenes from the clot. Furthermore, the surface-localized fibrinolytic activity also cleaves a variety of extracellular matrix proteins, thereby enabling S. pyogenes to migrate across barriers and disseminate within the host. This review summarizes the knowledge gained during the last two decades on the role of coagulation/fibrinolysis in host defense against S. pyogenes as well as the strategies developed by this pathogen to evade and exploit these host mechanisms for its own benefit.
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Affiliation(s)
- Torsten G Loof
- Infection Immunology Research Group, Helmholtz Centre for Infection Research Braunschweig, Germany
| | - Christin Deicke
- Infection Immunology Research Group, Helmholtz Centre for Infection Research Braunschweig, Germany
| | - Eva Medina
- Infection Immunology Research Group, Helmholtz Centre for Infection Research Braunschweig, Germany
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14
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Berends ETM, Kuipers A, Ravesloot MM, Urbanus RT, Rooijakkers SHM. Bacteria under stress by complement and coagulation. FEMS Microbiol Rev 2014; 38:1146-71. [PMID: 25065463 DOI: 10.1111/1574-6976.12080] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 06/23/2014] [Accepted: 07/14/2014] [Indexed: 02/03/2023] Open
Abstract
The complement and coagulation systems are two related protein cascades in plasma that serve important roles in host defense and hemostasis, respectively. Complement activation on bacteria supports cellular immune responses and leads to direct killing of bacteria via assembly of the Membrane Attack Complex (MAC). Recent studies have indicated that the coagulation system also contributes to mammalian innate defense since coagulation factors can entrap bacteria inside clots and generate small antibacterial peptides. In this review, we will provide detailed insights into the molecular interplay between these protein cascades and bacteria. We take a closer look at how these pathways are activated on bacterial surfaces and discuss the mechanisms by which they directly cause stress to bacterial cells. The poorly understood mechanism for bacterial killing by the MAC will be reevaluated in light of recent structural insights. Finally, we highlight the strategies used by pathogenic bacteria to modulate these protein networks. Overall, these insights will contribute to a better understanding of the host defense roles of complement and coagulation against bacteria.
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Affiliation(s)
- Evelien T M Berends
- Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
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15
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Chaikeeratisak V, Tassanakajon A, Armstrong PB. Interaction of pathogenic vibrio bacteria with the blood clot of the pacific white shrimp, Litopenaeus vannamei. THE BIOLOGICAL BULLETIN 2014; 226:102-10. [PMID: 24797092 DOI: 10.1086/bblv226n2p102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
In addition to its roles in hemostasis and wound repair, the blood clot plays an underappreciated role in innate immunity, where the established clot serves as a barrier to microbial penetration into the internal milieu and where the early clot entraps and immobilizes microbes that have entered wounds to the integuments. In this report we document the behavior of the pathogenic gram-negative bacterium Vibrio harveyi that has been entrapped in the fabric of the extracellular blood clot of one of its target organisms, the Pacific white shrimp, Litopenaeus vannamei. The freshly entrapped bacteria are held tightly by the clot, losing even Brownian motility, but by 1 h post-entrapment, a fraction of the bacteria have established small domains of fibrinolysis that enlarge progressively, enabling bacteria to escape from the clot's embrace. Escape is dependent on the actions of both serine- and metallo-proteases released from the bacterial cells.
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Affiliation(s)
- Vorrapon Chaikeeratisak
- Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093
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16
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Armstrong MT, Rickles FR, Armstrong PB. Capture of lipopolysaccharide (endotoxin) by the blood clot: a comparative study. PLoS One 2013; 8:e80192. [PMID: 24282521 PMCID: PMC3839915 DOI: 10.1371/journal.pone.0080192] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 09/30/2013] [Indexed: 12/13/2022] Open
Abstract
In vertebrates and arthropods, blood clotting involves the establishment of a plug of aggregated thrombocytes (the cellular clot) and an extracellular fibrillar clot formed by the polymerization of the structural protein of the clot, which is fibrin in mammals, plasma lipoprotein in crustaceans, and coagulin in the horseshoe crab, Limulus polyphemus. Both elements of the clot function to staunch bleeding. Additionally, the extracellular clot functions as an agent of the innate immune system by providing a passive anti-microbial barrier and microbial entrapment device, which functions directly at the site of wounds to the integument. Here we show that, in addition to these passive functions in immunity, the plasma lipoprotein clot of lobster, the coagulin clot of Limulus, and both the platelet thrombus and the fibrin clot of mammals (human, mouse) operate to capture lipopolysaccharide (LPS, endotoxin). The lipid A core of LPS is the principal agent of gram-negative septicemia, which is responsible for more than 100,000 human deaths annually in the United States and is similarly toxic to arthropods. Quantification using the Limulus Amebocyte Lysate (LAL) test shows that clots capture significant quantities of LPS and fluorescent-labeled LPS can be seen by microscopy to decorate the clot fibrils. Thrombi generated in the living mouse accumulate LPS in vivo. It is suggested that capture of LPS released from gram-negative bacteria entrapped by the blood clot operates to protect against the disease that might be caused by its systemic dispersal.
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Affiliation(s)
- Margaret T. Armstrong
- Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America
- Department of Molecular and Cellular Biology, University of California Davis, Davis, California, United States of America
| | - Frederick R. Rickles
- Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America
- Department of Medicine, School of Medicine, The George Washington University, Washington, DC, United States of America
| | - Peter B. Armstrong
- Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America
- Department of Molecular and Cellular Biology, University of California Davis, Davis, California, United States of America
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17
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Shawyer AC, Amaral JGPV, Langer JC. The role of tissue plasminogen activator in the management of complex intra-abdominal abscesses in children. J Pediatr Surg 2012; 47:1380-4. [PMID: 22813800 DOI: 10.1016/j.jpedsurg.2011.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Revised: 12/06/2011] [Accepted: 12/08/2011] [Indexed: 01/02/2023]
Abstract
OBJECTIVE The objective of this study is to assess the safety of fibrinolytic therapy using tissue plasminogen activator (tPA) in children with complex intra-abdominal abscesses. SUMMARY BACKGROUND DATA Intra-abdominal abscesses are common in children. Antibiotics and percutaneous drainage are the mainstays of treatment, but drainage may be less effective when the fluid is thick or septated. Fibrinolytic therapy using tPA is effective in a rat model of intra-abdominal abscesses, has recently been reported for the treatment of intra-abdominal abscesses in adults, and is commonly used in the treatment of empyema in children. METHODS This is a retrospective review of all patients over a 10-year period who had intra-abdominal collections managed with tPA abscess drainage. RESULTS Sixty-four children had a total of 66 drains placed and 92 doses of tPA. Appendicitis was the cause of the abscesses in 52 of 64 children. Mean length of stay pre-tPA was 11.7 ± 7.63 days, mean time from drain insertion to tPA was 4.3 ± 3.78 days, and mean time from tPA to discharge was 8.6 ± 8.85 days. Thirty patients underwent an operation before tPA administration. No patients experienced bleeding complications, anastomotic or appendiceal stump leak, or wound dehiscence after the administration of tPA, and no patients had abnormalities in coagulation studies related to tPA administration. One child died of sepsis. CONCLUSIONS Tissue plasminogen activator is safe for the management of thick or septated intra-abdominal abscesses in children. A prospective controlled study will be needed to evaluate the efficacy of this technique.
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Affiliation(s)
- Anna C Shawyer
- Division of Pediatric Surgery, Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
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18
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Concistrè G, Chiaramonti F, Miceli A, Glauber M. Mitral and aortic valve endocarditis caused by a rare pathogen: Streptococcus constellatus. Interact Cardiovasc Thorac Surg 2012; 14:889-90. [PMID: 22374286 DOI: 10.1093/icvts/ivs032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Streptococcus constellatus endocarditis is associated with systemic embolism and frequently with a poor prognosis. We describe the first case reported in the literature of infective endocarditis by penicillin-resistant S. constellatus causing both mitral and aortic valve regurgitation, treated successfully with double-valve replacement.
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Affiliation(s)
- Giovanni Concistrè
- Department of Adult Cardiac Surgery, G. Pasquinucci Heart Hospital, Fondazione CNR-G, Monasterio, Massa, Italy.
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19
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Zhang QY, Ma S, Xi D, Zhang WT, Li AW. Administration of a novel penicillamine-bound membrane: a preventive and therapeutic treatment for abdominal adhesions. BMC Surg 2011; 11:5. [PMID: 21349198 PMCID: PMC3053215 DOI: 10.1186/1471-2482-11-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2010] [Accepted: 02/25/2011] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Adhesions formation is a significant postsurgical complication. At present, there is no effective method for preventing adhesions formation 1, although barrier products such as Dextran (Dex) 2 and sodium hyaluronate (SH) 3 have proved the most clinically successful 456, This study is designed to investigate the preventive and therapeutic potential of a novel penicillamine-bound membrane for abdominal adhesions formation. METHODS 150 rats were involved in the present study. All animals were randomly divided into 6 groups (1 vehicle group and 5 test groups respectively treated with dextran, sodium hyaluronate, penicillamine, penicillamine-bound membrane or non-penicillamine-bound membrane). The occurrence, grade and score of abdominal adhesions were compared between the different groups. The breaking strength of incision was compared between the vehicle group and the penicillamine, membrane with/without penicillamine - treated groups. Expression of collagen type I was compared between the vehicle and penicillamine-treated group. The occurrence of adhesions was compared between the Dextran (Dex), sodium hyaluronate (SH), penicillamine-treated group and membrane with or without penicillamine- treated groups. RESULTS Penicillamine and penicillamine-bound membrane had significant preventive effects on abdominal adhesions formation, better than dextran, sodium hyaluronate and non-penicillamine-bound membrane. However, neither of them influenced incision healing, although they insignificantly decreased the breaking strength of the incision. Penicillamine-bound membrane, which can be loaded locally and more efficaciously, shows greater advantages than penicillamine. CONCLUSIONS Penicillamine-bound membrane can be applied as an effective therapeutic intervention for abdominal adhesions with inconsequential side effects.
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Affiliation(s)
- Qiang-Ye Zhang
- Department of Pediatric Surgery, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China
| | - Sheng Ma
- Qingzhou Clinical College, Weifang Medical University, China
| | - Dong Xi
- Department of Pediatric Surgery, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China
- Department of Pediatrics, The Children's Hospital of Philadelphia, 34thStreet and Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA
| | - Wen-Tong Zhang
- Department of Pediatric Surgery, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China
| | - Ai-Wu Li
- Department of Pediatric Surgery, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, Shandong, 250012, China
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20
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Sabbadini PS, Genovez MRN, Silva CFD, Adelino TLN, Santos CSD, Pereira GA, Nagao PE, Dias AADSDO, Mattos-Guaraldi AL, Hirata Júnior R. Fibrinogen binds to nontoxigenic and toxigenic Corynebacterium diphtheriae strains. Mem Inst Oswaldo Cruz 2010; 105:706-11. [DOI: 10.1590/s0074-02762010000500018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Accepted: 05/18/2010] [Indexed: 11/22/2022] Open
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21
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Fagotti A, Costantini B, Fanfani F, Vizzielli G, Rossitto C, Lecca A, Scambia G. Risk of Postoperative Pelvic Abscess in Major Gynecologic Oncology Surgery: One-Year Single-Institution Experience. Ann Surg Oncol 2010; 17:2452-8. [DOI: 10.1245/s10434-010-1059-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Indexed: 12/30/2022]
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22
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Gulla KC, Gupta K, Krarup A, Gal P, Schwaeble WJ, Sim RB, O'Connor CD, Hajela K. Activation of mannan-binding lectin-associated serine proteases leads to generation of a fibrin clot. Immunology 2010; 129:482-95. [PMID: 20002787 PMCID: PMC2842495 DOI: 10.1111/j.1365-2567.2009.03200.x] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2009] [Revised: 10/11/2009] [Accepted: 10/14/2009] [Indexed: 01/19/2023] Open
Abstract
The lectin pathway of complement is activated upon binding of mannan-binding lectin (MBL) or ficolins (FCNs) to their targets. Upon recognition of targets, the MBL-and FCN-associated serine proteases (MASPs) are activated, allowing them to generate the C3 convertase C4b2a. Recent findings indicate that the MASPs also activate components of the coagulation system. We have previously shown that MASP-1 has thrombin-like activity whereby it cleaves and activates fibrinogen and factor XIII. MASP-2 has factor Xa-like activity and activates prothrombin through cleavage to form thrombin. We now report that purified L-FCN-MASPs complexes, bound from serum to N-acetylcysteine-Sepharose, or MBL-MASPs complexes, bound to mannan-agarose, generate clots when incubated with calcified plasma or purified fibrinogen and factor XIII. Plasmin digestion of the clot and analysis using anti-D-dimer antibodies revealed that the clot was made up of fibrin and was similar to that generated by thrombin in normal human plasma. Fibrinopeptides A and B (FPA and FPB, respectively) were released after fibrinogen cleavage by L-FCN-MASPs complexes captured on N-acetylcysteine-Sepharose. Studies of inhibition of fibrinopeptide release indicated that the dominant pathway for clotting catalysed by the MASPs is via MASP-2 and prothrombin activation, as hirudin, a thrombin inhibitor that does not inhibit MASP-1 and MASP-2, substantially inhibits fibrinopeptide release. In the light of their potent chemoattractant effects on neutrophil and fibroblast recruitment, the MASP-mediated release of FPA and FPB may play a role in early immune activation. Additionally, MASP-catalysed deposition and polymerization of fibrin on the surface of micro-organisms may be protective by limiting the dissemination of infection.
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23
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Excreted/secreted proteins from trypanosome procyclic strains. J Biomed Biotechnol 2010; 2010:212817. [PMID: 20011064 PMCID: PMC2789517 DOI: 10.1155/2010/212817] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Accepted: 09/19/2009] [Indexed: 01/27/2023] Open
Abstract
Trypanosoma secretome was shown to be involved in parasite virulence and is suspected of interfering in parasite life-cycle steps such as establishment in the Glossina midgut, metacyclogenesis. Therefore, we attempted to identify the proteins secreted by procyclic strains of T. brucei gambiense and T. brucei brucei, responsible for human and animal trypanosomiasis, respectively.
Using mass spectrometry, 427 and 483 nonredundant proteins were characterized in T. brucei brucei and T. brucei gambiense secretomes, respectively; 35% and 42% of the corresponding secretome proteins were specifically secreted by T. brucei brucei and T. brucei gambiense, respectively, while 279 proteins were common to both subspecies. The proteins were assigned to 12 functional classes. Special attention was paid to the most abundant proteases (14 families) because of their potential implication in the infection process and nutrient supply. The presence of proteins usually secreted via an exosome pathway suggests that this type of process is involved in trypanosome ESP secretion.
The overall results provide leads for further research to develop novel tools for blocking trypanosome transmission.
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24
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Wang Z, Wilhelmsson C, Hyrsl P, Loof TG, Dobes P, Klupp M, Loseva O, Mörgelin M, Iklé J, Cripps RM, Herwald H, Theopold U. Pathogen entrapment by transglutaminase--a conserved early innate immune mechanism. PLoS Pathog 2010; 6:e1000763. [PMID: 20169185 PMCID: PMC2820530 DOI: 10.1371/journal.ppat.1000763] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Accepted: 01/12/2010] [Indexed: 11/18/2022] Open
Abstract
Clotting systems are required in almost all animals to prevent loss of body fluids after injury. Here, we show that despite the risks associated with its systemic activation, clotting is a hitherto little appreciated branch of the immune system. We compared clotting of human blood and insect hemolymph to study the best-conserved component of clotting systems, namely the Drosophila enzyme transglutaminase and its vertebrate homologue Factor XIIIa. Using labelled artificial substrates we observe that transglutaminase activity from both Drosophila hemolymph and human blood accumulates on microbial surfaces, leading to their sequestration into the clot. Using both a human and a natural insect pathogen we provide functional proof for an immune function for transglutaminase (TG). Drosophila larvae with reduced TG levels show increased mortality after septic injury. The same larvae are also more susceptible to a natural infection involving entomopathogenic nematodes and their symbiotic bacteria while neither phagocytosis, phenoloxidase or—as previously shown—the Toll or imd pathway contribute to immunity. These results firmly establish the hemolymph/blood clot as an important effector of early innate immunity, which helps to prevent septic infections. These findings will help to guide further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions. One of the main functions of immune systems is to prevent the dissemination of microbes and the resulting sepsis. Blood clotting during sepsis has until now been primarily regarded as harmful, leading to the formation of widespread clots in blood vessels and as a result to organ failure. Here we show that clotting also has a protective function to limit and prevent infections. This is achieved by capturing bacteria in the clot. Our infection studies were performed in the insect model Drosophila melanogaster where, due to the presence of an open circulatory system, the negative effects of clotting are less pronounced. We show that clotting of hemolymph—the insect blood equivalent—is essential in Drosophila to prevent septic death arising from injection of bacteria or infection with a natural pathogen. We also show that both Drosophila transglutaminase and its human homologue clotting factor XIII are key enzymes for sequestration of bacteria in the clot matrix, indicating the conserved nature of the clot's function in immunity. Our data are expected to lead to a much stronger appreciation of the role of blood clotting in innate immunity, and will guide future therapies which target this process.
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Affiliation(s)
- Zhi Wang
- Department of Molecular Biology and Functional Genomics, Stockholm University, Stockholm, Sweden
| | - Christine Wilhelmsson
- Department of Molecular Biology and Functional Genomics, Stockholm University, Stockholm, Sweden
| | - Pavel Hyrsl
- Department of Molecular Biology and Functional Genomics, Stockholm University, Stockholm, Sweden
- Department of Animal Physiology and Immunology, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic
| | - Torsten G. Loof
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Pavel Dobes
- Department of Molecular Biology and Functional Genomics, Stockholm University, Stockholm, Sweden
- Department of Animal Physiology and Immunology, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic
| | - Martina Klupp
- Department of Molecular Biology and Functional Genomics, Stockholm University, Stockholm, Sweden
| | - Olga Loseva
- Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden
| | | | - Jennifer Iklé
- Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Richard M. Cripps
- Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Heiko Herwald
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Ulrich Theopold
- Department of Molecular Biology and Functional Genomics, Stockholm University, Stockholm, Sweden
- * E-mail:
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25
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Buyne OR, Bleichrodt RP, De Man BM, Lomme RM, Verweij PE, van Goor H, Hendriks T. Tissue-type plasminogen activator prevents abscess formation but does not affect healing of bowel anastomoses and laparotomy wounds in rats with secondary peritonitis. Surgery 2009; 146:939-46. [DOI: 10.1016/j.surg.2009.04.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Accepted: 04/22/2009] [Indexed: 01/01/2023]
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26
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Ikeda A, Gabazza EC, Morser J, Imoto I, Kuroda M, D'Alessandro-Gabazza CN, Hara K, Ruiz DB, Bernabe PG, Katsurahara M, Toda M, Kobayashi Y, Yano Y, Sumida Y, Suzuki K, Taguchi O, Takei Y. Presence of thrombin-activatable fibrinolysis inhibitor in Helicobacter pylori-associated gastroduodenal disease. Helicobacter 2009; 14:147-55. [PMID: 19298343 DOI: 10.1111/j.1523-5378.2009.00662.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a role in the regulation of coagulation and inflammation. In addition to inhibiting the fibrinolytic system, TAFI may also regulate the bradykinin and complement systems. We hypothesized that TAFI also plays a role in defense mechanisms of the gastric mucosa during Helicobacter pylori infection. This study comprised 65 patients with gastroduodenal disorders: 41 patients with H. pylori infection, 13 without, and 11 patients with cured H. pylori infection. The gastric intramucosal concentrations of TAFI were measured by enzyme immunoassay. The gastric levels of TAFI and plasminogen activator inhibitor-1 were significantly increased in patients with H. pylori compared to those without infection or cured H. pylori. The presence of TAFI was detected in gastric mucosal epithelial cells. The concentration of TAFI was correlated with the degree of gastric mucosal atrophy, inflammation, and disease activity. These results show that TAFI is present in the gastric mucosa and that it may play a role in the pathogenesis of H. pylori infection-associated gastroduodenal disorders.
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Affiliation(s)
- Ayumi Ikeda
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan
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Buyne O, van Goor H, Bleichrodt R, Verweij P, Hendriks T. Both tissue-type plasminogen activator and urokinase prevent intraabdominal abscess formation after surgical treatment of peritonitis in the rat. Surgery 2008; 144:66-73. [DOI: 10.1016/j.surg.2008.03.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2007] [Accepted: 03/31/2008] [Indexed: 11/25/2022]
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Cheng D, Nagata KT, Yoon HC. Randomized Prospective Comparison of Alteplase versus Saline Solution for the Percutaneous Treatment of Loculated Abdominopelvic Abscesses. J Vasc Interv Radiol 2008; 19:906-11. [DOI: 10.1016/j.jvir.2008.03.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2007] [Revised: 03/06/2008] [Accepted: 03/10/2008] [Indexed: 11/30/2022] Open
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Intraabdominal Infections. Surgery 2008. [DOI: 10.1007/978-0-387-68113-9_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Mayilyan KR, Presanis JS, Arnold JN, Sim RB. Discrete MBL-MASP complexes show wide inter-individual variability in concentration: data from UK vs Armenian populations. Int J Immunopathol Pharmacol 2006; 19:567-80. [PMID: 17026842 DOI: 10.1177/039463200601900313] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Mannan-binding lectin (MBL) circulates in plasma in complex with MBL-associated serine proteases (MASP) -1, -2 and -3 and a smaller component, MAp19. When MBL binds to the surface of foreign material (microorganisms), MASP-1, -2, -3 are activated. MASP-2 then activates the complement system. MASP-1 and -3 may activate other (unidentified) systems. MBL levels, MBL-bound MASP-1 and MBL-bound MASP-2 activities have been evaluated in healthy individuals from UK and Armenian populations. MBL-bound MASP-2 activity declines in aging (P<0.04). MBL correlates with smoking (P<0.02). There were significant differences between the two populations in MBL-bound MASP-1 activity and in MBL, but no difference in MBL-bound MASP-2 activity. When MASP activities were normalised to MBL (i.e. MASP-1 activity/MBL, MASP-2 activity/MBL), normalised MASP-2 activity in UK individuals was more than 2 fold higher than in Armenians. The difference in normalised MASP-2 activity level between these two Caucasoid populations, suggests that concentration of the MBL-(MASP-2) complex, and therefore the function of activating complement, depends not only on the quantity of MBL in serum and its oligomeric state, but also on the quantity of MASP-2 in serum. It is likely that in individuals with high MBL concentration there is excess free MBL not occupied by MASPs, particularly not by MASP-2.
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Affiliation(s)
- K R Mayilyan
- MRC Immunochemistry Unit, Department of Biochemistry, Oxford University, Oxford, UK
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Buyne OR, Bleichrodt RP, Verweij PE, Groenewoud HMM, van Goor H, Hendriks T. A peritonitis model with low mortality and persisting intra-abdominal abscesses. Int J Exp Pathol 2006; 87:361-8. [PMID: 16965563 PMCID: PMC2517383 DOI: 10.1111/j.1365-2613.2006.00488.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Intra-abdominal abscesses are a potential source of recurrent or residual infection after surgical intervention for secondary peritonitis. The development of therapies requires a model which combines low mortality with the formation of persisting abscesses and which is also suitable to study the local inflammatory response. Male Wistar rats were injected intraperitoneally with a mixture of sterile rat faeces, increasing doses of E. coli (10(4)-10(8) cfu/ml) and a fixed dose of B. Fragilis (10(4) cfu/ml). After one h a laparotomy was performed and the peritoneal cavity was debrided. Blood samples were taken under anaesthesia after 6 and 24 h. Abdominal fluid samples were collected (by laparotomy) after 24 and 72 h. The rats were killed after 5 days and the abdomen was inspected for abscesses. Mortality was 90% in the two groups with the highest doses of E. coli and 30% in those with the two lowest doses. In the latter groups all surviving rats but one showed intraabdominal abscesses and bacteremia was encountered frequently, especially after 24 h in the 10(5) cfu E. coli group. The groups receiving 10(4)-10(6) cfu E. coli showed similar plasma IL-6 concentrations after 6 h which were lowered significantly after 24 h. No circulating TNF-alpha was found. Considerable concentrations of TNF-alpha, IL-6, IL-1beta, and IL-10, were found in the peritoneal fluid after 24 h but no differences were observed between the contro groups and those receiving 10(4)-10(6) cfu E. coli. At 72 h cytokine levels were reduced significantly and remained the highest in the animals dosed with 10(6) cfu E. coli. The present model is suitable to study the mechanisms involved in, and prevention of, intra-abdominal abscess formation after surgical treatment of generalized peritonitis.
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Affiliation(s)
- Otmar R Buyne
- Department of Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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van Veen SQ, Levi M, van Vliet AK, Florquin S, van Gulik TM, Boermeester MA. Peritoneal lavage with activated protein C alters compartmentalized coagulation and fibrinolysis and improves survival in polymicrobial peritonitis. Crit Care Med 2006; 34:2799-805. [PMID: 17006359 DOI: 10.1097/01.ccm.0000243795.04284.2a] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE During peritonitis, intra-abdominal fibrin entraps bacteria and hampers their elimination. Systemic administration of anticoagulant activated protein C improves survival in patients with severe sepsis, but its precise mode of action is unclear. This study in polymicrobial peritonitis assessed the effects of local activated protein C administration in peritoneal lavage fluid on coagulation, fibrinolysis, and survival. DESIGN Prospective, randomized study. SETTING University-based research laboratory. SUBJECTS C57BL/6 mice. INTERVENTIONS Twenty-four hours after induction of peritonitis by cecal ligation and puncture, mice underwent peritoneal lavage with activated protein C (1.0 microg/mL) or saline. Peritoneal lavage fluid, blood, and lungs were sampled after 24, 48, or 72 hrs (n = 8/group/time point). For survival analysis, maximum observation was 96 hrs (n = 22/group). Clotting time, tissue factor expression, thrombin-antithrombin complexes, fibrin degradation products (D-dimers), plasminogen activator, and plasminogen activator inhibitor were used to assess coagulation and fibrinolysis responses. MEASUREMENTS AND MAIN RESULTS Activated protein C lavage reduced abdominal bacterial load, abdominal and pulmonary clotting times, D-dimers (p < .05 vs. saline), pulmonary tissue factor expression, and fibrin depositions, without clear effects on systemic thrombin generation. Activated protein C lavage decreased plasma and abdominal tissue plasminogen activator levels with increased inhibitor plasminogen activator inhibitor-1 levels (p < .05) but had reverse effects on pulmonary fibrinolysis. Survival improved from 55% (saline) to 80% after intra-abdominal activated protein C administration (p = .03). CONCLUSIONS Peritoneal lavage with activated protein C may rebalance coagulation and fibrinolysis within compartments and improve survival in polymicrobial peritonitis.
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Affiliation(s)
- Suzanne Q van Veen
- Department of Surgery (Surgical Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Conrad ML, Pardy RL, Wainwright N, Child A, Armstrong PB. Response of the blood clotting system of the American horseshoe crab, Limulus polyphemus, to a novel form of lipopolysaccharide from a green alga. Comp Biochem Physiol A Mol Integr Physiol 2006; 144:423-8. [PMID: 16707269 DOI: 10.1016/j.cbpa.2006.03.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2005] [Revised: 03/17/2006] [Accepted: 03/24/2006] [Indexed: 11/19/2022]
Abstract
Lipopolysaccharide (LPS, endotoxin) is a component of Gram-negative bacteria and is the principal indicator to the innate immune systems of higher animals of a Gram-negative bacterial invasion. LPS activates the blood clotting system of the American horseshoe crab, Limulus polyphemus. By stimulating blood cell degranulation, LPS triggers the release of the proteins of the clotting system from the cells, and by activating a protease cascade that converts coagulogen, a soluble zymogen, to coagulin, the structural protein of the clot, LPS triggers the production of the fibrillar coagulin blood clot. Although originally thought to be restricted to the Gram-negative bacteria and the cyanobacteria, LPS, or a very similar molecule, has recently been described from a eukaryotic green alga, Chlorella. Here we show that, like LPS from Gram-negative bacteria, the algal molecule stimulates exocytosis of the Limulus blood cell and the clotting of coagulin. The coagulin clot efficiently entraps the cells of Chlorella in a network of fibrils. Invasion and erosion of the carapace by green algae is an important cause of mortality of Limulus, and it is suggested that the cellular response to aLPS may contribute to defense against this pathogen.
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Affiliation(s)
- Mara L Conrad
- Marine Biological Laboratory, 7 MBL Street, Woods Hole, MA 02543, USA
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Mullarky IK, Szaba FM, Winchel CG, Parent MA, Kummer LW, Mackman N, Johnson LL, Smiley ST. In situ assays demonstrate that interferon-gamma suppresses infection-stimulated hepatic fibrin deposition by promoting fibrinolysis. J Thromb Haemost 2006; 4:1580-7. [PMID: 16839357 PMCID: PMC3010163 DOI: 10.1111/j.1538-7836.2006.02010.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Inflammatory cytokines potently impact hemostatic pathways during infection, but the tissue-specific regulation of coagulation and fibrinolysis complicates studies of the underlying mechanisms. METHODS AND RESULTS Here, we describe assays that quantitatively measuring prothrombinase (PTase), protein C-ase (PCase) and plasminogen activator (PA) activities in situ, thereby facilitating studies of tissue-specific hemostasis. Using these assays, we investigate the mechanisms regulating hepatic fibrin deposition during murine toxoplasmosis and the means by which interferon-gamma (IFN-gamma) suppresses infection-stimulated fibrin deposition. We demonstrate that Toxoplasma infection upregulates hepatic PTase, PCase, and PA activity. Wild type and gene-targeted IFN-gamma-deficient mice exhibit similar levels of infection-stimulated PTase activity. By contrast, IFN-gamma-deficiency is associated with increased PCase activity and reduced PA activity during infection. Parallel analyses of hepatic gene expression reveal that IFN-gamma-deficiency is associated with increased expression of thrombomodulin (TM), a key component of the PCase, increased expression of thrombin-activatable fibrinolysis inhibitor (TAFI), a PC substrate, and reduced expression of urokinase PA (u-PA). CONCLUSIONS These findings suggest that IFN-gamma suppresses infection-stimulated hepatic fibrin deposition by suppressing TM-mediated activation of TAFI, thereby destabilizing fibrin deposits, and concomitantly increasing hepatic u-PA activity, thereby promoting fibrinolysis. We anticipate that further application of these in situ assays will improve our understanding of tissue-specific hemostasis, its regulation by cytokines, and its dysregulation during coagulopathy.
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Affiliation(s)
| | | | | | | | | | - Nigel Mackman
- Departments of Immunology and Cell Biology, The Scripps Research Institute, La Jolla, CA, USA
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Armstrong PB. Proteases and protease inhibitors: a balance of activities in host-pathogen interaction. Immunobiology 2006; 211:263-81. [PMID: 16697919 DOI: 10.1016/j.imbio.2006.01.002] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2005] [Accepted: 01/12/2006] [Indexed: 12/30/2022]
Abstract
The immune system is the collection of effector molecules and cells of the host that act against invading parasites and their products. Secreted proteases serve important roles in parasitic metabolism and virulence and the several families of protein protease inhibitors of the plasma and blood cells play an important role in immunity by inactivating and clearing the protease virulence factors of parasites. The protease inhibitors are of two classes, the active-site inhibitors and the alpha2-macroglobulins. Inhibitors for the first class bind and inactivate the active site of the target protease. Proteins of the second class bind proteases by a unique molecular trap mechanism and deliver the bound protease to a receptor-mediated endocytic system for degradation in secondary lysosomes. Proteins of the alpha2-macroglobulin family are present in a variety of animal phyla, including the nematodes, arthropods, mollusks, echinoderms, urochordates, and vertebrates. A shared suite of unique functional characteristics have been documented for the alpha2-macroglobulins of vertebrates, arthropods, and mollusks. The alpha2-macroglobulins of nematodes, arthropods, mollusks, and vertebrates show significant sequence identity in key functional domains. Thus, the alpha2-macroglobulins comprise an evolutionarily conserved arm of the innate immune system with similar structure and function in animal phyla separated by 0.6 billion years of evolution.
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Aydin C, Aytekin FO, Tekin K, Kabay B, Yenisey C, Kocbil G, Ozden A. Effect of Temporary Abdominal Closure on Colonic Anastomosis and Postoperative Adhesions in Experimental Secondary Peritonitis. World J Surg 2006; 30:612-9. [PMID: 16479336 DOI: 10.1007/s00268-005-0511-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND The effect of relaparotomies and temporary abdominal closure on colonic anastomoses and postoperative adhesions is under debate. METHODS In the experiments reported here, colonic anastomosis was constructed 24 hours after cecal ligation and puncture in rats that were divided into three groups of eight animals each. The abdomen was closed primarily in groups I and II, and a Bogota bag was used for abdominal closure in group III. At 24 hours following anastomosis, relaparotomy was performed only in group II and III rats, and the abdomen was closed directly in group II; after removal of the Bogota bag in group III animals, the abdomen was closed directly. On the fifth day of anastomotic construction, bursting pressures and tissue hydroxyproline content of the anastomoses, along with peritoneal adhesions, were assessed and compared. RESULTS Mean anastomotic bursting pressures and hydroxyproline contents did not differ among the groups. Median adhesion scores were significantly higher in group III than the other two groups. CONCLUSIONS Relaparotomy and the type of temporary closure have no negative effect on anastomotic healing in rats with peritonitis. Temporary abdominal closure with a Bogota bag caused a significantly high rate of adhesions.
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Affiliation(s)
- Cagatay Aydin
- Department of Surgery, Pamukkale University, School of Medicine, Kinikli, Denizli, 20070 Turkey.
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Mullarky IK, Szaba FM, Berggren KN, Kummer LW, Wilhelm LB, Parent MA, Johnson LL, Smiley ST. Tumor necrosis factor alpha and gamma interferon, but not hemorrhage or pathogen burden, dictate levels of protective fibrin deposition during infection. Infect Immun 2006; 74:1181-8. [PMID: 16428767 PMCID: PMC1360344 DOI: 10.1128/iai.74.2.1181-1188.2006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2005] [Revised: 10/10/2005] [Accepted: 11/29/2005] [Indexed: 01/23/2023] Open
Abstract
While coagulation often causes pathology during infectious disease, we recently demonstrated that fibrin, a product of the coagulation pathway, performs a critical protective function during acute toxoplasmosis (L. L. Johnson, K. N. Berggren, F. M. Szaba, W. Chen, and S. T. Smiley, J. Exp. Med. 197:801-806, 2003). Here, we investigate the mechanisms regulating the formation of this protective fibrin. Through comparisons of Toxoplasma-infected wild-type and cytokine-deficient mice we dissociate, for the first time, the relative fibrin-regulating capacities of pathogen products, host cytokines, and infection-stimulated hemorrhage. Remarkably, neither the pathogen burden nor hemorrhage is a primary regulator of fibrin levels. Rather, two type 1 cytokines exert dominant and counterregulatory roles: tumor necrosis factor alpha (TNF-alpha), acting via the type 1 TNF-alpha receptor, promotes fibrin deposition, while gamma interferon (IFN-gamma), acting via STAT1 and IFN-gamma receptors expressed on radioresistant cells, suppresses fibrin deposition. These findings have important clinical implications, as they establish that cytokines known to regulate pathological coagulation also dictate levels of protective fibrin deposition. We present a novel model depicting mechanisms by which the immune system can destroy infected tissue while independently restraining hemorrhage and promoting tissue repair through the deliberate deposition of protective fibrin.
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Affiliation(s)
- Isis K Mullarky
- Trudeau Institute, 154 Algonquin Ave., Saranac Lake, NY 12983, USA
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Renckens R, Roelofs JJTH, ter Horst SAJ, van 't Veer C, Havik SR, Florquin S, Wagenaar GTM, Meijers JCM, van der Poll T. Absence of thrombin-activatable fibrinolysis inhibitor protects against sepsis-induced liver injury in mice. THE JOURNAL OF IMMUNOLOGY 2006; 175:6764-71. [PMID: 16272333 DOI: 10.4049/jimmunol.175.10.6764] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Thrombin-activatable fibrinolysis inhibitor (TAFI), also known as carboxypeptidase R, has been implicated as an important negative regulator of the fibrinolytic system. In addition, TAFI is able to inactivate inflammatory peptides such as complement factors C3a and C5a. To determine the role of TAFI in the hemostatic and innate immune response to abdominal sepsis, TAFI gene-deficient (TAFI-/-) and normal wild-type mice received an i.p. injection with Escherichia coli. Liver TAFI mRNA and TAFI protein concentrations increased during sepsis. In contrast to the presumptive role of TAFI as a natural inhibitor of fibrinolysis, TAFI-/- mice did not show any difference in E. coli-induced activation of coagulation or fibrinolysis, as measured by plasma levels of thrombin-anti-thrombin complexes and D-dimer and the extent of fibrin depositions in lung and liver tissues. However, TAFI-/- mice were protected from liver necrosis as indicated by histopathology and clinical chemistry. Furthermore, TAFI-/- mice displayed an altered immune response to sepsis, as indicated by an increased neutrophil recruitment to the peritoneal cavity and a transiently increased bacterial outgrowth together with higher plasma TNF-alpha and IL-6 levels. These data argue against an important part for TAFI in the regulation of the procoagulant-fibrinolytic balance in sepsis and reveals a thus far unknown role of TAFI in the occurrence of hepatic necrosis.
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Chang AK, Kim HY, Park JE, Acharya P, Park IS, Yoon SM, You HJ, Hahm KS, Park JK, Lee JS. Vibrio vulnificus secretes a broad-specificity metalloprotease capable of interfering with blood homeostasis through prothrombin activation and fibrinolysis. J Bacteriol 2005; 187:6909-16. [PMID: 16199560 PMCID: PMC1251599 DOI: 10.1128/jb.187.20.6909-6916.2005] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Vibrio vulnificus is a causative agent of serious food-borne diseases in humans related to the consumption of raw seafood. It secretes a metalloprotease that is associated with skin lesions and serious hemorrhagic complications. In this study, we purified and characterized an extracellular metalloprotease (designated as vEP) having prothrombin activation and fibrinolytic activities from V. vulnificus ATCC 29307. vEP could cleave various blood clotting-associated proteins such as prothrombin, plasminogen, fibrinogen, and factor Xa, and the cleavage could be stimulated by addition of 1 mM Mn2+ in the reaction. The cleavage of prothrombin produced active thrombin capable of converting fibrinogen to fibrin. The formation of active thrombin appeared to be transient, with further cleavage resulting in a loss of activity. The cleavage of plasminogen, however, did not produce an active plasmin. vEP could cleave all three major chains of fibrinogen without forming a clot. It could cleave fibrin polymer formed by thrombin as well as the cross-linked fibrin formed by factor XIIIa. In addition, vEP could also cleave plasma proteins such as bovine serum albumin and gamma globulin, and its broad specificity is reflected in the cleavage sites, which include Asp207-Phe208 and Thr272-Ala273 bonds in prothrombin and a Tyr80-Leu81 bond in plasminogen. Taken together, the data suggest that vEP is a broad-specificity protease that could function as a prothrombin activator and a fibrinolytic enzyme to interfere with blood homeostasis as part of the mechanism associated with the pathogenicity of V. vulnificus in humans and thereby facilitate the development of systemic infection.
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Affiliation(s)
- Alan K Chang
- Research Center for Proteineous Materials, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, Republic of Korea
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Sikkink CJJM, Reijnen MMPJ, Falk P, van Goor H, Holmdahl L. Influence of monocyte-like cells on the fibrinolytic activity of peritoneal mesothelial cells and the effect of sodium hyaluronate. Fertil Steril 2005; 84 Suppl 2:1072-7. [PMID: 16209995 DOI: 10.1016/j.fertnstert.2005.03.078] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2004] [Revised: 05/13/2005] [Accepted: 05/13/2005] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To determine whether the presence of cells of the monocyte-macrophage system affects the fibrinolytic response of peritoneal mesothelial cells to lipopolysaccharide (LPS) in the presence and absence of sodium hyaluronate. DESIGN Controlled laboratory experiment. SETTING Cell cultures in an academic laboratory research environment. PATIENT(S) Human peritoneal mesothelial cells were harvested from patients undergoing a laparotomy for noninfectious reasons and were cultured in vitro. Co-cultures were formed by adding U-937 human monocyte-like cells to a monolayer of mesothelial cells. INTERVENTION(S) After 24 hours, cultures were treated with 10 ng/mL of LPS, and sodium hyaluronate was added in a final concentration of 0.2%. Controls received medium without sodium hyaluronate. MAIN OUTCOME MEASURE(S) After 24 hours' incubation, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) levels were determined in medium and cell lysates by using ELISA techniques. RESULT(S) In medium of co-cultures, tPA and PAI-1 concentrations were statistically significantly increased compared with the case of monocultures, whereas uPA concentration was statistically significantly decreased. In cell lysates of co-cultures, PAI-1 concentration was statistically significantly increased compared with the case of monocultures, whereas tPA and uPA were unaffected. Treatment with sodium hyaluronate statistically significantly decreased PAI-1 and uPA concentrations in medium of monocultures but decreased uPA concentration only in medium of co-cultures, compared with the case of controls. CONCLUSION(S) Cells of the monocyte-macrophage system modulate the fibrinolytic capacity of LPS treated human peritoneal mesothelial cells and interfere in the hyaluronan-associated changes in mesothelial fibrinolytic capacity.
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Mullarky IK, Szaba FM, Berggren KN, Parent MA, Kummer LW, Chen W, Johnson LL, Smiley ST. Infection-stimulated fibrin deposition controls hemorrhage and limits hepatic bacterial growth during listeriosis. Infect Immun 2005; 73:3888-95. [PMID: 15972474 PMCID: PMC1168549 DOI: 10.1128/iai.73.7.3888-3895.2005] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2005] [Revised: 02/24/2005] [Accepted: 03/12/2005] [Indexed: 02/04/2023] Open
Abstract
Bacterial infections are major causes of human mortality. The activation of coagulation pathways leading to the deposition of insoluble fibrin frequently accompanies bacterial infection, and much attention has focused upon the pathological attributes of infection-stimulated fibrin deposition. Nevertheless, here we present conclusive evidence that infection-stimulated fibrin deposition can perform critical protective functions during bacterial infection. Specifically, we demonstrate that coagulation-impaired fibrin(ogen)-deficient mice, in comparison with genetically matched control mice, display increased mortality upon peritoneal infection with the gram-positive facultative intracellular bacterium Listeria monocytogenes. To distinguish effects of fibrinogen from those of fibrin, we treat wild-type mice with warfarin, an anticoagulant that suppresses fibrin formation without impacting fibrinogen levels. Warfarin treatment exacerbates listeriosis, suggesting that fibrin is the key mediator of protection. With regard to the underlying protective mechanisms, we demonstrate that fibrin(ogen) suppresses anemia, reduces hemorrhagic pathology, and limits bacterial growth during listeriosis. Despite confirming a prior report that fibrin(ogen) promotes the peritoneal clearance of the extracellular bacterium Staphylococcal aureus, we demonstrate that fibrin(ogen) plays little role in controlling peritoneal numbers of L. monocytogenes bacteria or the dissemination of L. monocytogenes bacteria from the peritoneal cavity. Rather, fibrin(ogen) primarily limits the growth of these intracellular bacteria within hepatic tissue. While the pathological potential of excessive infection-stimulated fibrin deposition is well appreciated, our findings reveal that fibrin can function protectively, via multiple mechanisms, during bacterial infection.
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Affiliation(s)
- Isis K Mullarky
- Trudeau Institute, Saranac Lake, 154 Algonquin Avenue, Saranac Lake, New York 12983, USA
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Bae JS, Jang KH, Jin HK. Comparison of intraperitoneal anti-adhesive polysaccharides derived from Phellinus mushrooms in a rat peritonitis model. World J Gastroenterol 2005; 11:810-6. [PMID: 15682472 PMCID: PMC4250588 DOI: 10.3748/wjg.v11.i6.810] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the adhesion- and abscess-reducing capacities of various concentrations of polysaccharides derived from fungus, Phellinus gilvus (PG) or Phellinus linteus (PL) in a rat peritonitis model.
METHODS: In 96 SD rats, experimental peritonitis was induced using the cecal ligation and puncture model (CLP). Rats were randomly assigned to 8 groups; Ringer’s lactate solution (RL group), hyaluronic acid (HA group), 0.025%, 0.25%, and 0.5% polysaccharides from PG (PG0.025, 0.25, and 0.5 groups), and PL (PL0.025, 0.25, and 0.5 groups). Adhesions and abscesses were noted at 7 d after CLP. RT-PCR assay was performed to assess the cecal tissue.
RESULTS: Adhesion formation was significantly reduced in PG0.25, 0.5, PL0.25, 0.5, and HA groups (2.5±0.7, 2.4±0.7, 3.8±1.0, 3.6±0.8, and 2.7±1.1, P<0.05). The incidence of abscesses was significantly reduced in all treated groups compared to RL group (58%, P<0.05). The urokinase-type plasminogen activator (uPA) gene expression was greatly up-regulated by increasing the concentration of polysaccharides. The urokinase-type plasminogen activator receptor (uPAR) and tumor necrosis factor (TNF)-α mRNA were highly expressed in PG0.25, 0.5, PL0.25, and 0.5 groups.
CONCLUSION: We concluded that 0.5% polysaccharide derived from PG and PL was the optimal concentration in preventing adhesion and abscess formation and may act by modulating activity of uPA and TNF-α in a rat peritonitis model.
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Affiliation(s)
- Jae-Sung Bae
- Department of Surgery, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea
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Armstrong PB, Armstrong MT. The decorated clot: Binding of agents of the innate immune system to the fibrils of the limulus blood clot. THE BIOLOGICAL BULLETIN 2003; 205:201-203. [PMID: 14583529 DOI: 10.2307/1543252] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
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Diamond IR, Wales PW, Connolly B, Gerstle T. Tissue plasminogen activator for the treatment of intraabdominal abscesses in a neonate. J Pediatr Surg 2003; 38:1234-6. [PMID: 12891500 DOI: 10.1016/s0022-3468(03)00275-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Fibrinolytic agents have been used successfully in the management of loculated empyema; however, their use in the treatment of intraabdominal abscesses is limited. The authors describe the case of a 4-week-old girl with intraabdominal abscesses secondary to intestinal perforation that were not amenable to percutaneous drainage, but were managed successfully with intracavitary administration of tissue-plasminogen activator. This case represents the first report in a human, in which tissue-plasminogen activator was used to facilitate percutaneous drainage of an intraabdominal abscess. It is also the first time a fibrinolytic agent has been used for this purpose in a child.
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Affiliation(s)
- Ivan R Diamond
- Division of Pediatric General Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
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Reijnen MMPJ, Bleichrodt RP, van Goor H. Pathophysiology of intra-abdominal adhesion and abscess formation, and the effect of hyaluronan. Br J Surg 2003; 90:533-41. [PMID: 12734857 DOI: 10.1002/bjs.4141] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Intra-abdominal adhesions and abscesses cause significant morbidity and mortality. The formation of fibrin in the abdominal cavity is a common pathophysiological pathway for both. The aim of this review was to investigate the pathophysiology of intra-abdominal adhesions and abscesses, and to explore the possible sites of action of hyaluronan. METHODS Data were reviewed from the literature using the Medline database. RESULTS Both surgery and peritonitis disturb the equilibrium between coagulation and fibrinolysis in the abdominal cavity in favour of the coagulation system. Hyaluronan-based agents reduce adhesion formation after surgery. Moreover, hyaluronan solution reduces abscess formation in experimental peritonitis. Possible mechanisms of action include mechanical separation of wound surfaces, improvement of peritoneal healing, modulation of the inflammatory response and enhanced fibrinolysis. CONCLUSION Diminished fibrin degradation is a common pathway for the formation of adhesions and abscesses. The potential of hyaluronan-based agents to reduce intra-abdominal adhesions and abscesses in abdominal surgery and sepsis is a promising new concept. Elucidating the mechanisms involved and the clinical application of hyaluronan in peritonitis are challenges for future research.
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Affiliation(s)
- M M P J Reijnen
- Department of Surgery, University Medical Centre St Radboud, Nijmegen, The Netherlands.
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Armstrong PB, Quigley JP. A role for protease inhibitors in immunity of long-lived animals. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2002; 484:141-60. [PMID: 11418980 DOI: 10.1007/978-1-4615-1291-2_13] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2023]
Affiliation(s)
- P B Armstrong
- Department of Molecular and Cellular Biology, University of California, 1 Shields Ave, Davis, CA 95616, USA
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Otto BR, van Dooren SJM, Dozois CM, Luirink J, Oudega B. Escherichia coli hemoglobin protease autotransporter contributes to synergistic abscess formation and heme-dependent growth of Bacteroides fragilis. Infect Immun 2002; 70:5-10. [PMID: 11748157 PMCID: PMC127594 DOI: 10.1128/iai.70.1.5-10.2002] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Intra-abdominal infections (IAI) continue to be a serious clinical problem. Bacterial synergism is an important factor that influences the shift from contamination to IAI, leading to the development of lesions and abscess formation. Escherichia coli and Bacteroides fragilis are particularly abundant in IAI. The underlying molecular mechanisms of this pathogenic synergy are still unclear. The role of the hemoglobin protease (Hbp) autotransporter protein from E. coli in the synergy of IAI was investigated. Hbp is identical to Tsh, a temperature-sensitive hemagglutinin associated with avian pathogenic E. coli. Clinical isolates from miscellaneous extraintestinal infections were phenotypically and genotypically screened for Hbp. The presence of Hbp was significantly associated with E. coli isolated from IAI and other extraintestinal infections. In a murine infection model, Hbp was shown to contribute to the pathogenic synergy of abscess development. Mice immunized with Hbp were protected against mixed infections and did not develop abscess lesions. Furthermore, an E. coli wild-type strain that did not induce abscess formation in the synergy model was transformed with a plasmid encoding the hbp gene, and mixed infections with this strain lead to increased growth of B. fragilis and induction of abscess lesions. Growth-promoting studies showed that purified Hbp is able to deliver heme to B. fragilis strain BE1. In conclusion, results suggest the synergy of abscess formation by E. coli and B. fragilis can be partly explained by the capacity of B. fragilis to intercept Hbp and iron from heme to overcome the iron restrictions imposed by the host.
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Affiliation(s)
- Ben R Otto
- Department of Molecular Microbiology, Institute of Molecular Biological Sciences, Amsterdam, The Netherlands.
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Abstract
The colonization of a potential host by a parasite requires an ability to cross the integuments and then to escape from the host immune defenses. Proteinases are important virulence factors that assist these processes. Host proteinase inhibitors potentially contribute to immunity by inactivating the proteinase virulence factors of pathogens.
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Affiliation(s)
- P B Armstrong
- Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA.
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Modulation of hemostatic mechanisms in bacterial infectious diseases. Blood 2000. [DOI: 10.1182/blood.v96.7.2329.h8002329_2329_2337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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