Ischemia‐reperfusion injury is attenuated in VAP‐1‐deficient mice and by VAP‐1 inhibitors

Abstract

Neutrophils mediate the damage caused by ischemia-reperfusion both at the site of primary injury and in remote organs. Vascular adhesion protein-1 (VAP-1) is an ectoenzyme expressed on endothelial cells and it has been shown to regulate leukocyte extravasation. Here we show for the first time using VAP-1-deficient mice that VAP-1 plays a significant role in the intestinal damage and acute lung injury after ischemiareperfusion. Separate inhibition of VAP-1 by small molecule enzyme inhibitors and a function-blocking monoclonal antibody in WT mice revealed that the catalytic activity of VAP-1 is responsible for its pro-inflammatory action. The use of transgenic humanized VAP-1 mice also showed that the enzyme inhibitors alleviate both the ischemia-reperfusion injury in the gut and neutrophil accumulation in the lungs. These data thus indicate that VAP-1 regulates the inflammatory response in ischemia-reperfusion injury and suggest that blockade of VAP-1 may have therapeutic value.Key words: Adhesion molecules . Inflammation . Ischemia-reperfusion injury IntroductionInteraction between leukocytes and endothelium, which allows leukocyte extravasation to the tissues, forms an essential part of host defense. This interaction is mediated via adhesion molecules expressed on the surface of leukocytes and endothelium [1]. Although indispensable for normal immune response, increased leukocyte trafficking to the tissues has deleterious consequences in certain diseases [2][3][4][5].Diseases caused by ischemia are the leading cause of death in the developed countries. Since ischemia causes tissue necrosis, its treatment consists of restoration of blood flow to the ischemic tissue. Although reperfusion is necessary to prevent further damage to the ischemic tissue, it triggers an inflammatory response that aggravates ischemia-induced tissue damage [6]. Therefore, ischemia-reperfusion (IR) injury (IRI) complicates treatment of many potentially fatal diseases. A hallmark of IRI is sequestration of neutrophils in the reperfused tissues. Excessive neutrophil extravasation is to a large extent a consequence of increased expression and/or avidity of adhesion molecules on the surface of endothelial cells and neutrophils [1,7].Inflammatory response to IR can cause damage not only in reperfused tissues but also in remote organs. Pro-inflammatory cytokines released at the site of reperfusion enter circulation and activate endothelium and circulating leukocytes in multiple vascular beds [2,6]. Although systemic inflammatory response may lead to development of dysfunction anywhere in the body, lungs are the most frequently injured organ [8,9]. Indirect acute lung injury (ALI) can appear alone or as a part of multiple organ dysfunction syndrome, in which it is a strong independent risk factor for death [10]. Since increased leukocyte trafficking plays a major role in both IR and remote organ injury, identification of the molecules involved in neutrophil infiltration is of paramount importance for the development of an effective treatment. Va...

Local and remote tissue injury upon intestinal ischemia and reperfusion depends on the TLR/MyD88 signaling pathway

“…The local i-I/R injury may lead to a systemic inXammatory response, suggesting the release of mediators responsible for systemic inXammation and acute lung injury [3,4]. In fact, clinical and experimental evidences demonstrated an impairment of pulmonary function after i-I/R injury as a consequence of gut trauma [5,6]. Ischemic injury of the intestinal epithelium might account for bacterial translocation from the gut lumen leading to acute lung injury [7].…”

Reaction of Vascular Adhesion Protein-1 (VAP-1) with Primary Amines

“…As a consequence of the generation of products such as hydrogen peroxide, formaldehyde, and methylglyoxal, which are cytotoxic at high concentrations, the activity of VAP-1 has been linked to cellular damage, including atherosclerosis and vascular complications in diabetes (7,8). Ischemia-reperfusion injury in mice is attenuated through the use of VAP-1-specific inhibitors, and this is confirmed by genetic deletion of VAP-1 in mice (9). The activation of human lung VAP-1 by human plasma is greater if the plasma originates from diabetic patients or following heart myocardial infarction (10).…”

Galectin-3 Facilitates Neutrophil Recruitment as an Innate Immune Response to a Parasitic Protozoa Cutaneous Infection

“…In addition, depending on the affected tissue sites or the nature of the insult, neutrophils use different sets of molecules, which can differ from selectins and integrins, to facilitate migration from circulation to the affected sites (10, 14, 15, 18, 21-23, 25-29, 65). However, nonclassical molecules that can facilitate the migration have not been fully explored, and VAP-1 and galectin-3 are some of the few listed as candidates (32,34,(66)(67)(68)(69)(70)(71)(72).…”