Effects of mast cell membrane stabilizing agents in a rat lung ischemia-reperfusion model

Background. The aim of this study was to test the hypothesis that agents wh ich stabilize the mast cell membrane may modulate the phenotype of the vasc ular wall in a lung ischemia-reperfusion model, including altering expressi on of endothelial and leukocyte adhesion receptors and the inducible nitric oxide synthase (NOS-2). Methods. Three sets of rats were given either intravenous saline (group A), ketotifen (group B), or cromolyn (group C), respectively. The left pulmona ry artery was ligated temporarily and reopened after 2 hours of ischemia. T hen, after a 2-hour period of reperfusion, the left lung was excised. ICAM- 1 and NOS-2 were measured at the protein level by Western blotting, and cGM P levels were measured by enzyme-linked immunosorbent assay in the lung tis sue specimens for each drug group. Results. ICAM-1 expressions, determined as the intensity of a given band on the Western blot, were 197 +/- 59 in group B and 195 +/- 83 in group C ver sus 369 +/- 114 in group A (p = 0.002 for analysis of variance). In contras t with ICAM-1, NOS-2 expression was increased by ketotifen or cromolyn trea tment (464 +/- 82 in group B and 507 +/- 93 in group C, compared with 377 /- 44 for group A, p = 0.007). The finding of increased NOS-2 expression in groups B and C is consistent with the observed increase in tissue cGMP lev els in the same groups (1.92 +/- 0.9 pmol/ml for group A versus 7.8 +/- 3.5 pmol/ml for group B, and 12.4 +/- 5.8 pmol/ml for group C, p = 0.0004). Conclusions. These data establish that mast cell stabilizing agents modulat e the vascular phenotype in the setting of pulmonary ischemia and reperfusi on by decreasing ICAM-1 expression, augmenting expression of NOS-2, and inc reasing tissue cGMP levels. As decreasing ICAM-1 expression and increasing cGMP levels have proven useful to limit proinflammatory mechanisms of tissu e injury, mast cell stabilizing agents may provide a new therapeutic option to improve organ function in the setting of reperfusion. (C) 2000 by The S ociety of Thoracic Surgeons.