scholarly journals Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Theranostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 3781-3795 ◽  
Author(s):  
Marcela Garzón-Tituaña ◽  
José L Sierra-Monzón ◽  
Laura Comas ◽  
Llipsy Santiago ◽  
Tatiana Khaliulina-Ushakova ◽  
...  
Keyword(s):  
Abdominal Sepsis ◽  
Granzyme A

scholarly journals Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

2020 ◽  
Author(s):  
Marcela Garzón-Tituaña ◽  
José L Sierra-Monzón ◽  
Laura Comas ◽  
Llipsy Santiago ◽  
Tatiana Khaliulina-Ushakova ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Peritoneal Lavage ◽  
Therapeutic Potential ◽  
Bacterial Load ◽  
Cecal Ligation ◽  
Lavage Fluid ◽  
Abdominal Sepsis ◽  
Granzyme A ◽  
Severe Pathology ◽  
Deficient Mice

ABSTRACTSepsis is a serious syndrome characterised by a dysregulated systemic inflammatory response. Here we have analysed the role and the therapeutic potential of Granzyme A (GzmA) in the pathogenesis of peritoneal sepsis using the Cecal Ligation and Puncture (CLP) polymicrobial sepsis model and samples from humans undergoing abdominal sepsis.Elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen indicating that GzmA has no role in bacterial control. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα.Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis, and suggest that it could be targeted for treatment of this severe pathology.

Chronic Abdominal Sepsis and Migratory Polyarthritis

Rheumatology ◽  
1995 ◽  
Vol 34 (5) ◽  
pp. 478-479
Author(s):  
A. FAROOQI
Keyword(s):  
Abdominal Sepsis ◽  
Migratory Polyarthritis

scholarly journals Enterococcus faecalis exploits the human fibrinolytic system to drive excess collagenolysis: implications in gut healing and identification of druggable targets

2020 ◽  
Vol 318 (1) ◽  
pp. G1-G9 ◽  
Author(s):  
Richard A. Jacobson ◽  
Kiedo Wienholts ◽  
Ashley J. Williamson ◽  
Sara Gaines ◽  
Sanjiv Hyoju ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Healing Process ◽  
Abdominal Sepsis ◽  
Infectious Complications ◽  
Fibrinolytic System ◽  
Clinical Safety ◽  
High Concentrations ◽  
Clinically Significant

Perforations, anastomotic leak, and subsequent intra-abdominal sepsis are among the most common and feared complications of invasive interventions in the colon and remaining intestinal tract. During physiological healing, tissue protease activity is finely orchestrated to maintain the strength and integrity of the submucosa collagen layer in the wound. We (Shogan, BD et al. Sci Trans Med 7: 286ra68, 2015.) have previously demonstrated in both mice and humans that the commensal microbe Enterococcus faecalis selectively colonizes wounded colonic tissues and disrupts the healing process by amplifying collagenolytic matrix-metalloprotease activity toward excessive degradation. Here, we demonstrate for the first time, to our knowledge, a novel collagenolytic virulence mechanism by which E. faecalis is able to bind and locally activate the human fibrinolytic protease plasminogen (PLG), a protein present in high concentrations in healing colonic tissue. E. faecalis-mediated PLG activation leads to supraphysiological collagen degradation; in this study, we demonstrate this concept both in vitro and in vivo. This pathoadaptive response can be mitigated with the PLG inhibitor tranexamic acid (TXA) in a fashion that prevents clinically significant complications in validated murine models of both E. faecalis- and Pseudomonas aeruginosa-mediated colonic perforation. TXA has a proven clinical safety record and is Food and Drug Administration approved for topical application in invasive procedures, albeit for the prevention of bleeding rather than infection. As such, the novel pharmacological effect described in this study may be translatable to clinical trials for the prevention of infectious complications in colonic healing. NEW & NOTEWORTHY This paper presents a novel mechanism for virulence in a commensal gut microbe that exploits the human fibrinolytic system and its principle protease, plasminogen. This mechanism is targetable by safe and effective nonantibiotic small molecules for the prevention of infectious complications in the healing gut.

scholarly journals AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathaniel B. Bone ◽  
Eugene J. Becker ◽  
Maroof Husain ◽  
Shaoning Jiang ◽  
Anna A. Zmijewska ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Abdominal Sepsis ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Lung Infections ◽  
Sepsis Survivors ◽  
The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

scholarly journals Development of a minimal invasive and controllable murine model to study polymicrobial abdominal sepsis

All Life ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 265-276
Author(s):  
Folkert Steinhagen ◽  
Tobias Hilbert ◽  
Nina Cramer ◽  
Sebastian Senzig ◽  
Marijo Parcina ◽  
...  
Keyword(s):  
Murine Model ◽  
Abdominal Sepsis ◽  
Minimal Invasive

scholarly journals Genomic organization of the mouse granzyme A gene. Two mRNAs encode the same mature granzyme A with different leader peptides.

1992 ◽  
Vol 267 (35) ◽  
pp. 25488-25493
Author(s):  
R.J. Hershberger ◽  
H.K. Gershenfeld ◽  
I.L. Weissman ◽  
L Su
Keyword(s):  
Genomic Organization ◽  
Granzyme A ◽  
Leader Peptides

scholarly journals Tumor Suppressor NM23-H1 Is a Granzyme A-Activated DNase during CTL-Mediated Apoptosis, and the Nucleosome Assembly Protein SET Is Its Inhibitor

Cell ◽  
2003 ◽  
Vol 112 (5) ◽  
pp. 659-672 ◽  
Author(s):  
Zusen Fan ◽  
Paul J. Beresford ◽  
David Y. Oh ◽  
Dong Zhang ◽  
Judy Lieberman
Keyword(s):  
Tumor Suppressor ◽  
Nucleosome Assembly ◽  
Nucleosome Assembly Protein ◽  
Granzyme A

Intra-abdominal sepsis: the role of radiology

1991 ◽  
Vol 5 (3) ◽  
pp. 587-609 ◽  
Author(s):  
E.Jane Adam ◽  
Janet E. Page
Keyword(s):  
Abdominal Sepsis

Radicicol, an Hsp90 inhibitor, inhibits intestinal inflammation and leakage in abdominal sepsis

2013 ◽  
Vol 182 (2) ◽  
pp. 312-318 ◽  
Author(s):  
Yilin Zhao ◽  
Zheng-Jie Huang ◽  
Milladur Rahman ◽  
Qi Luo ◽  
Henrik Thorlacius
Keyword(s):  
Intestinal Inflammation ◽  
Abdominal Sepsis ◽  
Hsp90 Inhibitor

scholarly journals CE3 COST-EFFECTIVENESS OF POLYMYXIN B IMMOBILIZED FIBER COLUMN AND CONVENTIONAL MEDICAL THERAPY IN THE MANAGEMENT OF SEVERE ABDOMINAL SEPSIS IN ITALY

2010 ◽  
Vol 13 (3) ◽  
pp. A5
Author(s):  
P Berto ◽  
M Antonelli ◽  
C Ronco ◽  
D Cruz ◽  
RM Melotti
Keyword(s):  
Cost Effectiveness ◽  
Medical Therapy ◽  
Polymyxin B ◽  
Abdominal Sepsis ◽  
Conventional Medical Therapy
Sign in / Sign up

Export Citation Format

Share Document