scholarly journals Mitochondrial N-formyl peptides induce cardiovascular collapse and sepsis-like syndrome

2015 ◽  
Vol 308 (7) ◽  
pp. H768-H777 ◽  
Author(s):  
Camilla Ferreira Wenceslau ◽  
Cameron G. McCarthy ◽  
Theodora Szasz ◽  
Styliani Goulopoulou ◽  
R. Clinton Webb
Keyword(s):  
Nitric Oxide ◽  
Mast Cells ◽  
Hemorrhagic Shock ◽  
Formyl Peptide Receptor ◽  
Cardiovascular Collapse ◽  
Induced Hypotension ◽  
Severe Hypotension ◽  
Molecular Patterns ◽  
Formyl Peptides ◽  
Damage Associated Molecular Patterns

Fifty percent of trauma patients who present sepsis-like syndrome do not have bacterial infections. This condition is known as systemic inflammatory response syndrome (SIRS). A unifying factor of SIRS and sepsis is cardiovascular collapse. Trauma and severe blood loss cause the release of endogenous molecules known as damage-associated molecular patterns. Mitochondrial N-formyl peptides (F-MIT) are damage-associated molecular patterns that share similarities with bacterial N-formylated peptides and are potent immune system activators. The goal of this study was to investigate whether F-MIT trigger SIRS, including hypotension and vascular collapse via formyl peptide receptor (FPR) activation. We evaluated cardiovascular parameters in Wistar rats treated with FPR or histamine receptor antagonists and inhibitors of the nitric oxide pathway before and after F-MIT infusion. F-MIT, but not nonformylated peptides or mitochondrial DNA, induced severe hypotension via FPR activation and nitric oxide and histamine release. Moreover, F-MIT infusion induced hyperthermia, blood clotting, and increased vascular permeability. To evaluate the role of leukocytes in F-MIT-induced hypotension, neutrophil, basophil, or mast cells were depleted. Depletion of basophils, but not neutrophils or mast cells, abolished F-MIT-induced hypotension. Rats that underwent hemorrhagic shock increased plasma levels of mitochondrial formylated proteins associated with lung damage and antagonism of FPR ameliorated hemorrhagic shock-induced lung injury. Finally, F-MIT induced vasodilatation in isolated resistance arteries via FPR activation; however, F-MIT impaired endothelium-dependent relaxation in the presence of blood. These data suggest that F-MIT may be the link among trauma, SIRS, and cardiovascular collapse.

scholarly journals Two Sides of the Coin: Mast Cells as a Key Regulator of Allergy and Acute/Chronic Inflammation

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1615
Author(s):  
Zhongwei Zhang ◽  
Yosuke Kurashima
Keyword(s):  
Mast Cells ◽  
Chronic Inflammation ◽  
Regulatory Function ◽  
Type I ◽  
Allergic Reactions ◽  
Novel Approach ◽  
Molecular Patterns ◽  
Regulatory Functions ◽  
Damage Associated Molecular Patterns ◽  
Two Sides

It is well known that mast cells (MCs) initiate type I allergic reactions and inflammation in a quick response to the various stimulants, including—but not limited to—allergens, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). MCs highly express receptors of these ligands and proteases (e.g., tryptase, chymase) and cytokines (TNF), and other granular components (e.g., histamine and serotonin) and aggravate the allergic reaction and inflammation. On the other hand, accumulated evidence has revealed that MCs also possess immune-regulatory functions, suppressing chronic inflammation and allergic reactions on some occasions. IL-2 and IL-10 released from MCs inhibit excessive immune responses. Recently, it has been revealed that allergen immunotherapy modulates the function of MCs from their allergic function to their regulatory function to suppress allergic reactions. This evidence suggests the possibility that manipulation of MCs functions will result in a novel approach to the treatment of various MCs-mediated diseases.

SARM1mediates TLR9-induced vascular hyperpermeability following hemorrhagic shock

2018 ◽  
Vol 6 (3) ◽  
pp. 264-279
Author(s):  
Morrison R. Doelle ◽  
Benjamin M. Predmore
Keyword(s):  
Hemorrhagic Shock ◽  
Causes Of Death ◽  
Multiple Organ ◽  
In Vivo Model ◽  
Wild Type ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Significant Health ◽  
Necrosis Factor

Hemorrhagic shock (HS) result in multiple organ dysfunction syndrome (MODS) and inflammatory response. It is one of the world's leading causes of death within the first 40 years of life and thus a significant health problem. The exact mechanism is not clear. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including trauma and hemorrhagic shock. In the present study, we investigated whether the SARM1 responsible for mediats-TLR9-induces inflammatory process and vascular hyperpermeability following hemorrhagic shock. Here we produced an in vivo model of severe hemorrhagic shock in adult wild type mice (40 ± 2 mmHg for 90 min, fluid resuscitation for 30 min) was employed. Mesenteric postcapillary venules were examined for changes in hyperpermeability by intravital microscopy. Blood samples were collected for measurement of tumor necrosis factor (TNF) using ELISA. Biopsies were obtained from organs for light microscopic examination. Our data suggest that SARM1 promising a new mechanisim of TLR9 involved in regulation of hemorrhagic shock and therapeutic target for the treatment of hemorrhagic shock.

scholarly journals Damage-associated molecular patterns in resuscitated hemorrhagic shock are mitigated by peritoneal fluid administration

2018 ◽  
Vol 315 (3) ◽  
pp. L339-L347
Author(s):  
Paul J. Matheson ◽  
Mark A. Eid ◽  
Matthew A. Wilson ◽  
Victoria S. Graham ◽  
Samuel A. Matheson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Hemorrhagic Shock ◽  
Tissue Injury ◽  
High Mobility ◽  
Primary Response ◽  
Sprague Dawley ◽  
Shed Blood ◽  
Lung Blood Flow ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Conventional resuscitation (CR) of hemorrhagic shock (HS), a significant cause of trauma mortality, is intravenous blood and fluids. CR restores central hemodynamics, but vital organ flow can drop, causing hypoperfusion, hypoxia, damage-associated molecular patterns (DAMPs), and remote organ dysfunction (i.e., lung). CR plus direct peritoneal resuscitation (DPR) prevents intestinal and hepatic hypoperfusion. We hypothesized that DPR prevents lung injury in HS/CR by altering DAMPs. Anesthetized male Sprague-Dawley rats were randomized to groups ( n = 8/group) in one of two sets: 1) sham (no HS, CR, or DPR), 2) HS/CR (HS = 40% mean arterial pressure (MAP) for 60 min, CR = shed blood + 2 volumes normal saline), or 3) HS/CR + DPR. The first set underwent whole lung blood flow by colorimetric microspheres. The second set underwent tissue collection for Luminex, ELISAs, and histopathology. Lipopolysaccharide (LPS) and DAMPs were measured in serum and/or lung, including cytokines, hyaluronic acid (HA), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 protein (MYD88), and TIR-domain-containing adapter-inducing interferon-β (TRIF). Statistics were by ANOVA and Tukey-Kramer test with a priori P < 0.05. HS/CR increased serum LPS, HA, HMGB1, and some cytokines [interleukin (IL)-1α, IL-1β, IL-6, and interferon-γ]. Lung TLR4 and MYD88 were increased but not TRIF compared with Shams. HS/CR + DPR decreased LPS, HA, cytokines, HMGB1, TLR4, and MYD88 levels but did not alter TRIF compared with HS/CR. The data suggest that gut-derived DAMPs can be modulated by adjunctive DPR to prevent activation of lung TLR-4-mediated processes. Also, DPR improved lung blood flow and reduced lung tissue injury. Adjunctive DPR in HS/CR potentially improves morbidity and mortality by downregulating the systemic DAMP response.

scholarly journals The Role of DAMPS in Burns and Hemorrhagic Shock Immune Response: Pathophysiology and Clinical Issues. Review

2021 ◽  
Vol 22 (13) ◽  
pp. 7020
Author(s):  
Desirè Pantalone ◽  
Carlo Bergamini ◽  
Jacopo Martellucci ◽  
Giovanni Alemanno ◽  
Alessandro Bruscino ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Multiorgan Failure ◽  
Inflammatory Cells ◽  
Tissue Perfusion ◽  
Severe Burns ◽  
Catabolic State ◽  
Long Time ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Severe or major burns induce a pathophysiological, immune, and inflammatory response that can persist for a long time and affect morbidity and mortality. Severe burns are followed by a “hypermetabolic response”, an inflammatory process that can be extensive and become uncontrolled, leading to a generalized catabolic state and delayed healing. Catabolism causes the upregulation of inflammatory cells and innate immune markers in various organs, which may lead to multiorgan failure and death. Burns activate immune cells and cytokine production regulated by damage-associated molecular patterns (DAMPs). Trauma has similar injury-related immune responses, whereby DAMPs are massively released in musculoskeletal injuries and elicit widespread systemic inflammation. Hemorrhagic shock is the main cause of death in trauma. It is hypovolemic, and the consequence of volume loss and the speed of blood loss manifest immediately after injury. In burns, the shock becomes evident within the first 24 h and is hypovolemic-distributive due to the severely compromised regulation of tissue perfusion and oxygen delivery caused by capillary leakage, whereby fluids shift from the intravascular to the interstitial space. In this review, we compare the pathophysiological responses to burns and trauma including their associated clinical patterns.

scholarly journals Exogenous nitric oxide prevents cardiovascular collapse during hemorrhagic shock

Resuscitation ◽  
2011 ◽  
Vol 82 (5) ◽  
pp. 607-613 ◽  
Author(s):  
Parimala Nachuraju ◽  
Adam J. Friedman ◽  
Joel M. Friedman ◽  
Pedro Cabrales
Keyword(s):  
Nitric Oxide ◽  
Hemorrhagic Shock ◽  
Cardiovascular Collapse ◽  
Exogenous Nitric Oxide

scholarly journals Cellular and Immunohistochemical Changes in Anaphylactic Shock Induced in the Ovalbumin-Sensitized Wistar Rat Model

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 101
Author(s):  
Suhail Al-Salam ◽  
Elhadi H. Aburawi ◽  
Suleiman Al-Hammadi ◽  
Sekhar Dhanasekaran ◽  
Mohamed Shafiuallah ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mast Cell ◽  
Mast Cells ◽  
Small Bowel ◽  
Nitric Oxide Synthase ◽  
Rat Model ◽  
Anaphylactic Shock ◽  
Wistar Rat ◽  
Severe Hypotension ◽  
Oxide Synthase

Anaphylactic shock (AS) is a life-threatening, multisystem disorder arising from sudden release of mast cell- and basophil-derived mediators into the circulation. In this study, we have used a Wistar rat model to investigate AS-associated histopathologic changes in various organs. Rats were sensitized with ovalbumin (1 mg s.c), and AS was induced by intravenous injection of ovalbumin (1 mg). Experimental groups included nonallergic rats (n = 6) and allergic rats (n = 6). Heart rate and blood pressure were monitored during one hour. Organs were harvested at the end of the experiment and prepared for histologic and immunohistochemical studies. Lung, small bowel mucosa and spleen were found to undergo heavy infiltration by mast cells and eosinophils, with less prominent mast cell infiltration of cardiac tissue. The mast cells in lung, small bowel and spleen exhibited increased expression of tryptase, c-kit and induced nitric oxide synthase (iNOS). Increased expression of endothelial nitric oxide synthase (eNOS) by vascular endothelial cells was noted principally in lung, heart and small bowel wall. The Wistar rat model of AS exhibited accumulation of mast cells and eosinophils in the lung, small bowel, and spleen to a greater extent than in the heart. We conclude that lung and gut are principal inflammatory targets in AS, and likely contribute to the severe hypotension of AS. Targeting nitric oxide (NO) production may help reduce AS mortality.

scholarly journals Release mechanisms of major DAMPs

APOPTOSIS ◽  
2021 ◽  
Vol 26 (3-4) ◽  
pp. 152-162
Author(s):  
Atsushi Murao ◽  
Monowar Aziz ◽  
Haichao Wang ◽  
Max Brenner ◽  
Ping Wang
Keyword(s):  
Rna Binding ◽  
High Mobility ◽  
Live Cells ◽  
Membrane Channel ◽  
Membrane Rupture ◽  
Underlying Mechanisms ◽  
Shock Proteins ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Secretory Lysosomes

AbstractDamage-associated molecular patterns (DAMPs) are endogenous molecules which foment inflammation and are associated with disorders in sepsis and cancer. Thus, therapeutically targeting DAMPs has potential to provide novel and effective treatments. When establishing anti-DAMP strategies, it is important not only to focus on the DAMPs as inflammatory mediators but also to take into account the underlying mechanisms of their release from cells and tissues. DAMPs can be released passively by membrane rupture due to necrosis/necroptosis, although the mechanisms of release appear to differ between the DAMPs. Other types of cell death, such as apoptosis, pyroptosis, ferroptosis and NETosis, can also contribute to DAMP release. In addition, some DAMPs can be exported actively from live cells by exocytosis of secretory lysosomes or exosomes, ectosomes, and activation of cell membrane channel pores. Here we review the shared and DAMP-specific mechanisms reported in the literature for high mobility group box 1, ATP, extracellular cold-inducible RNA-binding protein, histones, heat shock proteins, extracellular RNAs and cell-free DNA.

scholarly journals Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kiran Todkar ◽  
Lilia Chikhi ◽  
Véronique Desjardins ◽  
Firas El-Mortada ◽  
Geneviève Pépin ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mitochondrial Proteins ◽  
Control Mechanisms ◽  
Mitochondrial Content ◽  
Sorting Nexin ◽  
Inflammatory Conditions ◽  
Selective Targeting ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Insight Into

AbstractMost cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson’s disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.

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