scholarly journals Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis

2016 ◽  
Vol 4 (1) ◽  
Author(s):  
Mizuki Hattori ◽  
Mitsuaki Yamazaki ◽  
Wakana Ohashi ◽  
Satoshi Tanaka ◽  
Kohshi Hattori ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Critical Role ◽  
Endogenous Histamine ◽  
Organ Tissue

THE ROLE OF MYELOPEROXIDASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S4-S4
Author(s):  
Belal Chami ◽  
Gulfam Ahmad ◽  
Angie Schroder ◽  
Patrick San Gabriel ◽  
Paul Witting
Keyword(s):  
Disease Severity ◽  
Hypochlorous Acid ◽  
Tissue Injury ◽  
Activity Index ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Sodium Sulphate ◽  
Host Tissue ◽  
Neutrophil Extracellular Trap

Abstract Neutrophils are short-lived immune cells that represent the major cell type recruited to the inflamed bowel releasing their azurophilic granules containing enzymes myeloperoxidase (MPO). Fecal and serum MPO levels has previously been shown to correlate to disease severity in IBD patients. MPO, in the presence of H2O2 and free Cl- undergoes a halogenation cycle, yielding the two-electron oxidant, hypochlorous acid (HOCl) - a potent bactericidal agent. However, chronic intestinal exposure to MPO/HOCl due to perpetual inflammation may cause secondary host-tissue injury and cell death. Neutrophil Extracellular Trap (NET)osis is a specialised form of neutrophil death where MPO is entrapped in a DNA scaffold and continues to elicit HOCl activity and may further contribute to host-tissue injury. We investigated the presence of NETs in surgically excised ileum samples from CD and healthy patients using advanced confocal microscopic techniques and found MPO, Neutrophil Elastase (NE) and Citrullinated Histone h3 (CitH3) - critical components of NET formation, individually positively correlate to the severity of histopathological intestinal injury. Furthermore, multiplex Opal™ IHC performed using LMS880 Airyscan-moduled microscopy with z-stacking revealed colocalization of NE, MPO, CitH3 and DAPI indicating the extensive presence of NETs in severely affected CD tissue. Using two pharmacological inhibitors of MPO in a dextran sodium sulphate (DSS) model of murine colitis, we demonstrated the pathological role of MPO in experimental colitis. MPO inhibitors, TEMPOL and AZD3241 delivered via daily i.p significantly rescued the course of colitis by abrogating clinical indices including body weight loss, disease activity index, inhibiting serum peroxidation, and preserving colon length, while significantly mitigating histoarchitectural damage associated with DSS-induced colitis. We also showed that MPO inhibition decreased neutrophil migration to the gut, suggesting MPO may play a role in perpetuating the inflammatory cell by further recruiting cells to the inflamed gut. Collectively, we have shown for the first time that MPO is not only an important clinical marker of disease severity but may also play a critical role in perpetuating host-tissue damage and inflammation.

The integrin alphavbeta6 is critical for keratinocyte migration on both its known ligand, fibronectin, and on vitronectin

1998 ◽  
Vol 111 (15) ◽  
pp. 2189-2195 ◽  
Author(s):  
X. Huang ◽  
J. Wu ◽  
S. Spong ◽  
D. Sheppard
Keyword(s):  
Cell Migration ◽  
Tissue Injury ◽  
Critical Role ◽  
Cell Behavior ◽  
Wild Type ◽  
Migration Assays ◽  
And Migration ◽  
Hepatocyte Growth

The integrin alphavbeta6 is expressed on a variety of epithelial cells during dynamic processes including organogenesis, tissue injury and malignant transformation. However, because of the lack of tools to specifically inhibit the function of this integrin, little is known about its effects on cell behavior. To directly examine the role of this integrin in cell migration, we used keratinocytes derived from wild-type mice or mice expressing a null mutation in the beta6 subunit (beta6-/-) to perform migration assays in vitro. Migration on the known alphavbeta6 ligand, fibronectin was reduced in keratinocytes from beta6-/- mice. Interestingly, keratinocytes from beta6-/- mice also demonstrated markedly reduced migration on vitronectin, a protein not previously known to be a ligand for alphavbeta6. An anti-alphavbeta6 monoclonal antibody 10D5, generated by immunization of beta6-/- mice with murine keratinocytes, inhibited adhesion and migration of wild-type keratinocyte on both vitronectin and fibronectin to levels similar to those seen with keratinocytes from beta6-/- mice. alphavbeta6-mediated migration on both ligands was dramatically augmented by treatment with phorbol myrisate acetate (PMA) or with hepatocyte growth factor, and augmentation of migration by either stimulus could be abolished by the PKC inhibitor GF109203X, suggesting a critical role for PKC in enhancement of alphavbeta6-mediated cell migration.

scholarly journals The Role of the Mineralocorticoid Receptor in Inflammation: Focus on Kidney and Vasculature

2017 ◽  
Vol 46 (4) ◽  
pp. 298-314 ◽  
Author(s):  
Zachary Belden ◽  
Jeffrey A. Deiuliis ◽  
Mirela Dobre ◽  
Sanjay Rajagopalan
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Smooth Muscle ◽  
Mineralocorticoid Receptor ◽  
Tissue Injury ◽  
Muscle Tone ◽  
Target Organ Damage ◽  
Critical Role ◽  
Macrophage Phenotype

Background: The remarkable success of clinical trials in mineralocorticoid receptor (MR) inhibition in heart failure has driven research on the physiological and pathological role(s) of nonepithelial MR expression. MR is widely expressed in the cardiovascular system and is a major determinant of endothelial function, smooth muscle tone, vascular remodeling, fibrosis, and blood pressure. An important new dimension is the appreciation of the role MR plays in immune cells and target organ damage in the heart, kidney and vasculature, and in the development of insulin resistance. Summary: The mechanism for MR activation in tissue injury continues to evolve with the evidence to date suggesting that activation of MR results in a complex repertoire of effects involving both macrophages and T cells. MR is an important transcriptional regulator of macrophage phenotype and function. Another important feature of MR activation is that it can occur even with normal or low aldosterone levels in pathological conditions. Tissue-specific conditional models of MR expression in myeloid cells, endothelial cells, smooth muscle cells and cardiomyocytes have been very informative and have firmly demonstrated a critical role of MR as a key pathophysiologic variable in cardiac hypertrophy, transition to heart failure, adipose inflammation, and atherosclerosis. Finally, the central nervous system activation of MR in permeable regions of the blood-brain barrier may play a role in peripheral inflammation. Key Message: Ongoing clinical trials will help clarify the role of MR blockade in conditions, such as atherosclerosis and chronic kidney disease.

scholarly journals C3b-Independent Complement Activation in Ischemia/Reperfusion Mesenteric Tissue Injury in Autoimmune Prone (B6.MRL/lpr) Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
J. Tofferi ◽  
S. Peng ◽  
C. M. Moratz
Keyword(s):  
Lupus Erythematosus ◽  
Complement Activation ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cobra Venom ◽  
Cobra Venom Factor ◽  
Inflammatory Tissue

Complement plays a critical role in the development of tissue injury in systemic lupus erythematosus. The B6.MRL/lpr mouse, an autoimmune prone mouse, exhibits accelerated and intensified tissue injury in the ischemia/reperfusion (IR) model. It has been demonstrated in nonautoimmune mice that inhibition of complement attenuates inflammatory tissue injury in IR models. The role of complement is not as clear in the B6.MRL/lpr strain. B6.MRL/lpr-C3 deficient animals are susceptible to injury, but long-term use of C3 inhibitors in B6.MRL/lpr-C3 competent animals restrained the development of nephritis. To clarify the role of complement in the B6.MRL/lpr strain, initial and midpathway inhibitors were evaluated. C1 inhibition attenuated tissue injury, thrombin deposition, and C5a generation in the B6.MRL/lpr strain. Downstream of C1 inhibition of C3 activation by administration of cobra venom factor suppressed IR injury in immune competent mice, but was not as effective in B6.MRL/lpr mice. C3 levels in both strains were decreased after cobra venom factor treatment; however, C5a generation, thrombin deposition, and tissue injury were observed in the B6.MRL/lpr strain. These studies suggest that in the B6.MRL/lpr autoimmune prone strain C1 activation leads to C3-dependent and C3-independent pathways of complement activation.

Role of expression IL-23 pathway in myocardial injury after global ischemia and reperfusion/cross talk with IL-17

2020 ◽  
Vol 8 (1) ◽  
pp. 21-33
Author(s):  
Ling Ogiku ◽  
Runqiu Fujii
Keyword(s):  
Epithelial Cells ◽  
Myocardial Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cell Types ◽  
Global Ischemia ◽  
Neutrophil Accumulation ◽  
Close Proximity

Myocardial injury caused by global ischemia/reperfusion is a complicated pathophysiological course, in which inflammation is thought to play an important role. Endothelial dysfunction plays a critical role in the pathogenesis of reperfusion injury in the myocardium. This role stems from the close proximity of the endothelium to neutrophils and other inflammatory cell types at the vascular interface during the critical early phase as well as the later phase of reperfusion. IL-17A is a cytokine expressed by a variety of cells in response to inflammatory cytokines that are released following tissue injury and/or inflammation. IL-17A induces epithelial cells to secrete neutrophil chemoattractants. The cytokine IL-23, which can be produced by epithelial cells, plays an important role in IL-17A production. Global myocardial injury induced by abdominal heart transplant model in IL-17A deficient (Il17a-/-), IL-23R deficient (Il23r-/-) and WT mice. Our data showed that cTn-I, neutrophil accumulation MCP-1 and ICAM-1 were significantly less in both Il17a-/- mice and Il23r/- mice than in WT controls. These two pathways may become possible therapeutic targets for the treatment of global ischemia induced myocardial injury.

Role of peroxisome proliferator activator receptor-gamma (PPAR-γ) in lung sepsis

2014 ◽  
Vol 2 (4) ◽  
pp. 228-246
Author(s):  
Dan G. Wang ◽  
Nasser Ghaly Yousif
Keyword(s):  
Lung Tissue ◽  
Mononuclear Cells ◽  
Tissue Injury ◽  
Critical Role ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Mice Model ◽  
Clinical Value ◽  
Ppar Γ

PPAR-gamma has been implicated in the pathology of numerous diseases including; obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine). In the present study, to directly determine the role of PPARγ in lung sepsis we used PPARγ-knockout and C57/BL6 mice model. Mice are treated with Lipopolysaccharide LPS (0.5 mg/kg, iv) for 6-hours, the plasma and tissue cytokines TNF-α, IL-1β, IL-6, IL-10, MIP-1 and KC are analyzed by ELISA. The infiltrations of the mononuclear cells in the lung tissue and degree of lung tissue injury are examined using immunofluorescent and histopathology staining respectively. In PPARγ-knockout mice, LPS induced more expression of pro-inflammatory cytokines expression, which was associated with a marked monocyte infiltration, tissue injury and elevated lung activity of myeloperoxidase compared with wild type C57/BL6 mice. Present study, suggests that PPARγ has a critical role in attenuate lung sepsis and further study need to elucidate the clinical value.

Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment

2021 ◽  
Author(s):  
Zhao Shan ◽  
Leike Li ◽  
Constance Lynn Atkins ◽  
Meng Wang ◽  
Yankai Wen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Tissue Injury ◽  
Critical Role ◽  
Molecular Pathways ◽  
Mechanistic Studies ◽  
Wild Type ◽  
Critical Pathway ◽  
Podoplanin Expression ◽  
Platelet Accumulation

Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. The present study unveiled a critical role of chitinase 3-like-1 (Chi3l1) in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chi3l1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of CD44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chi3l1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chi3l1-/- mice, but not in CD44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Overall, we uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.

scholarly journals IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

2020 ◽  
Author(s):  
AL Chenery ◽  
S Rosini ◽  
JE Parkinson ◽  
JA Herrera ◽  
Craig Lawless ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Stress Responses ◽  
Tissue Injury ◽  
Critical Role ◽  
Lung Damage ◽  
Surfactant Protein D ◽  
Nippostrongylus Brasiliensis ◽  
Tissue Remodelling

AbstractIL-13 plays a key role during protective type 2 immune responses at mucosal sites, such as during infection with nematodes. However, dysregulation of IL-13 can also contribute to the pathogenesis of atopic and fibrotic diseases such as allergic asthma. Matrix remodelling is an important component of repair processes in the lung but also a hallmark of chronic conditions involving fibrosis. Hence, understanding the role of IL-13 in tissue remodelling has important clinical implications. Since IL-13 shares receptors and signalling pathways with IL-4, disentangling the relative contributions of these type 2 cytokines has been challenging. Additionally, little is known about the singular role of IL-13 following acute tissue injury. In this study, we used Nippostrongylus brasiliensis infection as a model of acute lung tissue damage comparing responses between WT and IL-13-deficient mice, in which IL-4 signalling is intact. Importantly, we found that IL-13 played a critical role in limiting tissue injury and haemorrhaging in the lung following infection. Through proteomic and transcriptomic profiling, we identified IL-13-dependent changes in matrix and associated regulators. We further showed that IL-13 is required for the induction of epithelial-derived type 2 effector molecules such as RELM-α and surfactant protein D. Pathway analyses predicted that IL-13 was heavily involved in the induction of cellular stress responses and regulation of lung epithelial cell differentiation by suppression of Foxa2 pathways. Thus, we propose that IL-13 has tissue-protective functions during lung injury and regulates epithelial cell responses during type 2 immunity in this acute setting.

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