Role of neutrophils in ischemia-reperfusion-induced microvascular injury

Abstract

Recent studies indicate that polymorphonuclear neutrophils (PMNs) infiltrate the intestinal mucosa during ischemia and after reperfusion. To determine whether PMNs mediate the increased microvascular permeability produced by ischemia-reperfusion (I/R) we treated cats with either saline, antineutrophil serum (ANS), or a monoclonal antibody specific for the beta-chain of the CD18 complex (MoAb 60.3) that prevents neutrophil adherence and extravasation. Intestinal microvascular permeability to plasma proteins was measured in control preparations (0.08 +/- 0.007), in preparations subjected to 1 h of ischemia then reperfusion (I/R, 0.32 +/- 0.02), I/R preparations treated with ANS (0.13 +/- 0.01), and I/R preparations treated with MoAb (0.12 +/- 0.003). Our results indicate that both PMN depletion (to less than 10% control) and prevention of PMN adherence significantly attenuate the increased microvascular permeability induced by I/R. These findings, coupled to previous results obtained from this model, support the hypothesis that neutrophils, which accumulate in the mucosa in response to xanthine oxidase activation, mediate the oxyradical-dependent injury produced by reperfusion of the ischemic bowel.

Leukocyte transendothelial migration: A local affair

“…Some studies propose leukocyte adhesion and transmigration to be acute events leading to tissue damage and organ failure during inflammation and ischemia-reperfusion. 37,38 A strong argument that supports this hypothesis are the neutrophil depletion or CD11/CD18 blocking experiments that have been shown to attenuate vascular injury under inflammatory and ischemia-reperfusion conditions. [38][39][40][41] However, when microvascular permeability was measured simultaneously with leukocyte-endothelial interactions, local plasma leakage sites were distinct from those of leukocyte adhesion or transmigration.…”

Comparative anti‐inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury

“…This is particularly true as the neutropaenia, resulting in global sequestration or tissue margination in the animal, may be indirectly related to the anti-inflammatory effects of the C3aRA in intestinal I/R. Studies employing strategies that deplete neutrophils directly (Hernandez et al, 1987) or inhibit their adhesion to the local tissue endothelium (Hernandez et al, 1987;Koike et al, 1995) report attenuation of intestinal I/R. These results strongly implicate the accumulation of neutrophils, activated by numerous mediators including C5a, in the microvasculature and their subsequent infiltration into the intestinal tissue and other sites (e.g.…”

“…A number of chemical and cellular mediators, including reactive oxygen species (Zimmerman & Granger, 1994), platelet-activating factor Sun et al, 2000), cytokines (tumour necrosis factor-a (TNF-a) and interleukin-6) (Sorkine et al, 1995;Yao et al, 1996;Sun et al, 1999), mucosal mast cells (Kanwar & Kubes, 1994;Kanwar et al, 1998) and polymorphonuclear leukocytes (PMNs) (Hernandez et al, 1987;Sisley et al, 1994;Koike et al, 1995) have been implicated in the pathogenesis of intestinal I/R. In addition, activation of the complement system, which results in production of the biologically active anaphylatoxins, complement factors 3a (C3a), 4a and 5a (C5a), has been demonstrated to play a significant role in the pathology of I/R (Riedemann & Ward, 2003).…”

Ischaemia-reperfusion injury in photodynamic therapy-treated mouse tumours

“…Ischaemia-reperfusion (I/R) injury is known as a potent instigator of inflammatory response responsible for severe tissue damage in a variety of common pathological conditions, including stroke, myocardial infarction, pulmonary and haemorrhagic shock, acute kidney and liver failure, and organ transplant rejection (Hernandez et al, 1987;Zimmerman and Granger, 1994;De Greef et al, 1998). Tissue ischaemia is associated with the conversion of xanthine dehydrogenase into oxidant-producing xanthine oxidase (XO), while concomitantly hypoxanthine accumulates because of the breakdown of ATP (Parks et al, 1988;Zimmerman and Granger, 1994).…”

“…At the time of reperfusion, sudden reintroduction of oxygen enables XO to induce the formation of xanthine from hypoxanthine, which is accompanied with an intense release of reactive oxygen species, primarily superoxide anion (Parkins et al, 1998). The induced oxidative stress at the level of vascular endothelium promotes complement activation and elicits a series of inflammatory events culminating in a massive invasion of activated neutrophils and other inflammatory cells into the previously ischaemic area (Hernandez et al, 1987;De Greef et al, 1998;Kilgore et al, 1999).…”