Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins

Abstract

Intestinal ischemia-reperfusion (I-R) is associated with lung injury and the acute respiratory distress syndrome. The hypothesis of this study was that intestinal I-R activates circulating neutrophils to promote elastase-mediated lung injury. Isolated rat lungs were perfused with blood or plasma obtained after intestinal I-R, and lung neutrophil retention and injury and bronchoalveolar lavage (BAL) elastase were measured. Perfusion with I-R blood caused lung neutrophil accumulation and injury and increased BAL elastase. These effects were attenuated by the elastase inhibitor L-658758. Interference with neutrophil adherence before gut reperfusion blocked BAL elastase accumulation. The role of endothelial junction proteins (cadherins) in I-R-elicited lung damage was also evaluated. Activated human neutrophils proteolyzed cadherins in human umbilical vein endothelial cells. Furthermore, plasma of patients with acute respiratory distress syndrome contained soluble cadherin fragments. The results of this study suggest that the elastase released by systemically activated neutrophils contributes to lung neutrophil accumulation and pulmonary microvascular injury. Elastase-mediated proteolysis of endothelial cell cadherins may represent the mechanism through which lung microvascular integrity is disrupted after intestinal I-R.

Targeting neutrophil elastase in cystic fibrosis

“…NE has broad substrate specificity and is capable of degrading a wide range of extracellular matrix proteins including elastin, collagen (types I-IV), fibronectin, laminin, and proteolglycans [33][34][35][36][37]. Other extracellular matrix proteins degraded include platelet IIb/IIIa receptor, complement receptor, thrombomodulin, lung surfactant, and cadherins [38][39][40][41][42]. In addition, NE can cleave coagulation factors (fibrinogen and factors V, VII, XII, and XIII), plasminogen, IgG, IgA, and IgM, complement factors C3 and C5, complement receptors, and gp120, the coat protein of the human immunodeficiency virus [43][44][45].…”

Identification of Proteases Involved in the Proteolysis of Vascular Endothelium Cadherin during Neutrophil Transmigration

“…Other studies indicate that these junctional complexes disrupt under the action of neutrophil-derived proteases, thus facilitating neutrophil migration (30,34).…”

“…This is in conflict with the results of Cepinskas et al (30), who found that, on migrating neutrophils, membranebound elastase, which localizes to the migrating front, facilitates transendothelial migration. Moreover, in some pathological situations, administration of an elastase inhibitor attenuates the transmigration of neutrophils (34).…”

In vivo efficacy of sivelestat in combination with pazufloxacin againstLegionellapneumonia

“…The findings in the SIV+PZFX mice seemed to be the most effectively improved. Because NE can degrade proteoglycans in the glycocalyx and components of the endothelial basement membrane [24], the combination therapy may inhibiting the vicious cycle. Thus, NE can partly play a role in the pathogenesis in L.…”