Mast cell proteases and inflammation

Dai, Hongji; Korthuis, Ronald J.

doi:10.1016/j.ddmod.2011.06.004

Cited by 44 publications

(44 citation statements)

References 48 publications

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“…Mast cells are tissue-resident inflammatory cells that are strategically localized close to blood vessels and neurons of most organs, being especially numerous in connective tissues and at mucosal surfaces of the airways and GI tract, allowing them to perform a sentinel function (170, 659, 749, 869). They contain numerous cytoplasmic granules that are filled with a large number of preformed proinflammatory mediators, including proteases, histamine, and serotonin, angiotensin II, and cytokines such as TNFα that are released on degranulation (170).…”

Section: Cell Types Involved In Postischemic Inflammationmentioning

confidence: 99%

“…They contain numerous cytoplasmic granules that are filled with a large number of preformed proinflammatory mediators, including proteases, histamine, and serotonin, angiotensin II, and cytokines such as TNFα that are released on degranulation (170). Within minutes of activation, mast cells also synthesize and release arachidonate-derived lipid mediators (170).…”

Section: Cell Types Involved In Postischemic Inflammationmentioning

confidence: 99%

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Ischemia/Reperfusion

Kalogeris

Baines

Krenz

et al. 2016

Comprehensive Physiology

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Ischemic disorders, such as myocardial infarction, stroke, and peripheral vascular disease, are the most common causes of debilitating disease and death in westernized cultures. The extent of tissue injury relates directly to the extent of blood flow reduction and to the length of the ischemic period, which influence the levels to which cellular ATP and intracellular pH are reduced. By impairing ATPase-dependent ion transport, ischemia causes intracellular and mitochondrial calcium levels to increase (calcium overload). Cell volume regulatory mechanisms are also disrupted by the lack of ATP, which can induce lysis of organelle and plasma membranes. Reperfusion, although required to salvage oxygen-starved tissues, produces paradoxical tissue responses that fuel the production of reactive oxygen species (oxygen paradox), sequestration of proinflammatory immunocytes in ischemic tissues, endoplasmic reticulum stress, and development of postischemic capillary no-reflow, which amplify tissue injury. These pathologic events culminate in opening of mitochondrial permeability transition pores as a common end-effector of ischemia/reperfusion (I/R)-induced cell lysis and death. Emerging concepts include the influence of the intestinal microbiome, fetal programming, epigenetic changes, and microparticles in the pathogenesis of I/R. The overall goal of this review is to describe these and other mechanisms that contribute to I/R injury. Because so many different deleterious events participate in I/R, it is clear that therapeutic approaches will be effective only when multiple pathologic processes are targeted. In addition, the translational significance of I/R research will be enhanced by much wider use of animal models that incorporate the complicating effects of risk factors for cardiovascular disease.

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Section: Cell Types Involved In Postischemic Inflammationmentioning

confidence: 99%

Section: Cell Types Involved In Postischemic Inflammationmentioning

confidence: 99%

Ischemia/Reperfusion

Kalogeris

Baines

Krenz

et al. 2016

Comprehensive Physiology

Self Cite

643

565

View full text Add to dashboard Cite

show abstract

“…Instant release of MC-specific proteases and proinflammatory mediators, such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), from intracellular stores are not only critical in local tissue injury but can also rapidly elicit systemic effects, due to the close proximity of MCs to blood vessels. 8, 9 …”

Section: Introductionmentioning

confidence: 99%

Intestinal Mast Cells Mediate Gut Injury and Systemic Inflammation in a Rat Model of Deep Hypothermic Circulatory Arrest*

Karhausen

Gibson

et al. 2013

Critical Care Medicine

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Background Cardiac surgery, especially when employing cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA), is associated with systemic inflammatory responses that significantly affect morbidity and mortality. Intestinal perfusion abnormalities have been implicated in such responses, but the mechanisms linking local injury and systemic inflammation remain unclear. Intestinal mast cells (MC) are specialized immune cells that secrete various preformed effectors in response to cellular stress. We hypothesized that MCs are activated in a microenvironment shaped by intestinal ischemia/reperfusion (I/R), and investigated local and systemic consequences in a rat model of DHCA. Methods and Results Adult rats were cooled to 16-18°C on CPB before instituting DHCA for 45 minutes. Specimens were harvested following rewarming and 2 hours of recovery. Significant intestinal barrier disruption was found, together with macro- and microscopic evidence of I/R injury in ileum and colon but not in lungs or kidneys. Immunofluorescence and toluidine blue staining revealed MC hyperplasia and activation in the gut. Pretreatment with the MC stabilizer cromolyn sodium efficiently blocked MC degranulation and resulted in preserved intestinal morphology and barrier function following DHCA. Furthermore, cromolyn sodium treatment dramatically reduced intestinal neutrophil influx and systemic release of various proinflammatory cytokines. Conclusions Our data provides primary evidence that intestinal I/R is a leading pathophysiologic process in a rat model of DHCA and that intestinal injury and local and systemic inflammatory responses are critically dependent on MC activation. This identifies intestinal MCs as central players in DHCA-associated responses, and opens novel therapeutic possibilities for patients undergoing this procedure.

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“…Characteristic features of postcapillary venular responses to I/R include enhanced oxidant production, leukocyte rolling and stationary adhesion, transendothelial leukocyte migration, platelet-leukocyte aggregation, platelet/endothelial cell adhesion, and protein extravasation. Mast cells and macrophages also release substances that can amplify the inflammatory response to I/R (Boros, Kaszaki & Nagy, 1991; Bortolotto, Morrison, Han & Messina, 2004; Dai & Korthuis, 2011; Granger & Korthuis, 1995; Granger 2003; Kalogeris et al 2012; Kalogeris et al, 2016; Kanwar & Kubes, 1994; Kanwar & Kubes, 2004; Kanwar, Hickey & Kubes, 1998; Steiner, Gonzalez & Wood; 1985). Neutrophil recruitment in response to I/R occurs by a complex, highly dynamic and well-coordinated series of steps, as depicted in Figure 1.…”

Section: Leukocyte-mediated Postischemic Endothelial Dysfunction In Amentioning

confidence: 99%

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

Korthuis

2018

Advances in Pharmacology

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Ischemia/reperfusion (I/R) induces leukocyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated dilatory responses (EDD) in upstream arterioles. A large body of evidence has implicated reactive oxygen species (ROS), adherent leukocytes, and proteases in postischemic EDD dysfunction in conduit arteries. However, arterioles represent the major site for the regulation of vascular resistance, but have received less attention with regard to the mechanisms underlying their reduced responsiveness to EDD stimuli in I/R. Even though leukocytes do not roll along, adhere to, or emigrate across arteriolar endothelium in postischemic intestine, recent work indicates that I/R-induced venular LECA is causally linked to EDD in arterioles. An emerging body of evidence supports the view that I/R-induced EDD in arterioles occurs by a mechanism that is triggered by LECA in postcapillary venules and involves the formation of signals in the interstitium elicited by the proteolytic activity of emigrated leukocytes. This activity releases matricryptins from or exposes matricryptic sites in the extracellular matrix (ECM) that interact with the integrin αvβ3 to induce mast cell chymase-dependent formation of angiotensin II (Ang II). Subsequent activation of NAD(P)H oxidase by Ang II leads to the formation of oxidants which inactivate NO, resulting in arteriolar EDD dysfunction. ROS generation also promotes eNOS uncoupling in the vascular wall, exacerbating impaired EDD responses. This work establishes new links between LECA in postcapillary venules, signals generated in the interstitium by emigrated leukocytes, mast cell degranulation, and impaired EDD in upstream arterioles. Given the importance of the endothelium in regulating vascular tone, these fundamentally important findings have enormous implications for our understanding of blood flow dysregulation in conditions characterized by I/R.

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Mast cell proteases and inflammation

Cited by 44 publications

References 48 publications

Ischemia/Reperfusion

Ischemia/Reperfusion

Intestinal Mast Cells Mediate Gut Injury and Systemic Inflammation in a Rat Model of Deep Hypothermic Circulatory Arrest*

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction

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