Protective Effects of Anti-Neutrophil Antibody against Myocardial Ischemia/Reperfusion Injury in Rats

Abstract

Neutrophil activation initiates myocardial ischemia/reperfusion (I/R) injuries. The aim of this study is to evaluate the in vitro functions of an anti-neutrophil monoclonal antibody, Urge-8, and its therapeutic efficacy against myocardial ischemia (MI) in rats. We measured in vitro functions of rat neutrophils including chemotactic activity, superoxide production, phagocytic function, and neutrophil degranulation. MI was induced in Wistar rats by clamping the left coronary artery for 1 h. Rats received either isotype-negative control IgG₁ (control group, n = 20), 250 µg/kg of Urge-8 before (pre-treatment group, n = 20) or after (post-treatment group, n = 20) MI. The three groups were compared during the first 24 h after reperfusion with respect to changes in mean arterial pressure, heart rate, body temperature, biochemistry, serum cytokines, myocardial neutrophil infiltration, survival rate, and size of MI. Urge-8 effectively suppressed in vitro functions of rat neutrophils including chemotactic activity, superoxide production, phagocytic function, and neutrophil degranulation. The Urge-8 treated groups showed higher levels of arterial pressure and survival rate, lower values of interleukin-6 and interleukin-8, lower grade of myocardial neutrophil infiltration, and smaller MI size as compared to the control group. In conclusion, Urge-8 is effective against myocardial I/R injury by suppressing certain functions and myocardial infiltration of neutrophils in rats.

A Novel ELR-CXC Chemokine Antagonist Reduces Intestinal Ischemia Reperfusion-Induced Mortality, and Local and Remote Organ Injury

“…This suggested that blockade of all ELR-CXC chemokines with an effective CXCR1/CXCR2 antagonist could be highly protective in I/R injury. On the other hand, antagonizing alternate neutrophil ligands (e.g., C5a, LTB4, and PAF) reportedly only partially inhibits neutrophil-mediated I/R injury [30][31][32]. Despite the reports of a critical role for neutrophils in intestinal I/R injury, there are reports that depleting circulating neutrophils before experimental induction of I/R injury does not reduce either local or remote organ injury [33], and that macrophage depletion, instead, substantially ameliorates pathology [34].…”

Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium

“…Prior research has revealed that PMN recruitment in postischemic myocardium plays a key role in producing cardiac injury. Multiple studies show that attenuated postischemic cardiac PMN sequestration significantly reduces infarct size and improves cardiac contractile function (26,29,30,39). Rui and colleagues (42) presented important evidence recently that suggests that cardiomyocytes in reperfusing myocardium may be an important source of peptides that generate interstitial-to-blood chemotactic gradients that promote trans- HIF-1, a potent ␣␤ transcription factor, mediates tissue responses to hypoxia.…”

The balance between the production of tumor necrosis factor-alpha and interleukin-10 determines tissue injury and lethality during intestinal ischemia and reperfusion

“…However, reperfusion of ischemic tissues is associated with local and systemic leukocyte activation and trafficking (specially neutrophil), endothelial barrier dysfunction in postcapillary venules, enhanced production of inflammatory mediators and great lethality (Lefer & Lefer 1996, Granger 1999, Carden & Granger 2000. This phenomenon has been referred to as "reperfusion injury" and several studies have demonstrated that injury is dependent on neutrophil recruitment (Jaeschke et al 1990, Weight et al 1996, Xiao et al 1997, Kyriakides et al 1999, Souza et al 2000a, b, Baxter 2002, Kohtani et al 2002, Merchant et al 2003. Activated neutrophils contribute to tissue damage through several mechanisms: (i) release of free radicals following the respiratory burst of the NADPH oxidase system; (ii) release of proteolytic enzymes; (iii) stimulation of cytokine release from local cells, thus promoting further neutrophil recruitment and, finally (iv) plugging of capilares by neutrophils contribute to the no-flow phenomenon (Ambrosio & Tritto 1999, Jordan et al 1999, Vermeiren et al 2000.…”