K M Vural1, H Liao, M C Oz, D J Pinsky. 1. Department of Cardiothoracic Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, USA. kvural@tr-net.net.tr
Abstract
BACKGROUND: The aim of this study was to test the hypothesis that agents which stabilize the mast cell membrane may modulate the phenotype of the vascular wall in a lung ischemia-reperfusion model, including altering expression 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 pulmonary artery was ligated temporarily and reopened after 2 hours of ischemia. Then, 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 cGMP levels were measured by enzyme-linked immunosorbent assay in the lung tissue 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 versus 369+/-114 in group A (p = 0.002 for analysis of variance). In contrast with ICAM-1, NOS-2 expression was increased by ketotifen or cromolyn treatment (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 levels 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 modulate the vascular phenotype in the setting of pulmonary ischemia and reperfusion by decreasing ICAM-1 expression, augmenting expression of NOS-2, and increasing tissue cGMP levels. As decreasing ICAM-1 expression and increasing cGMP levels have proven useful to limit proinflammatory mechanisms of tissue injury, mast cell stabilizing agents may provide a new therapeutic option to improve organ function in the setting of reperfusion.
BACKGROUND: The aim of this study was to test the hypothesis that agents which stabilize the mast cell membrane may modulate the phenotype of the vascular wall in a lung ischemia-reperfusion model, including altering expression 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 pulmonary artery was ligated temporarily and reopened after 2 hours of ischemia. Then, 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 cGMP levels were measured by enzyme-linked immunosorbent assay in the lung tissue 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 versus 369+/-114 in group A (p = 0.002 for analysis of variance). In contrast with ICAM-1, NOS-2 expression was increased by ketotifen or cromolyn treatment (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 levels 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 modulate the vascular phenotype in the setting of pulmonary ischemia and reperfusion by decreasing ICAM-1 expression, augmenting expression of NOS-2, and increasing tissue cGMP levels. As decreasing ICAM-1 expression and increasing cGMP levels have proven useful to limit proinflammatory mechanisms of tissue injury, mast cell stabilizing agents may provide a new therapeutic option to improve organ function in the setting of reperfusion.
Authors: Weili Zhang; Amanda L Chancey; Huei-Ping Tzeng; Zhenqing Zhou; Kory J Lavine; Feng Gao; Natarajan Sivasubramanian; Philip M Barger; Douglas L Mann Journal: Circulation Date: 2011-10-24 Impact factor: 29.690
Authors: Ellen L Hughes; Felix Becker; Roderick J Flower; Julia C Buckingham; Felicity N E Gavins Journal: Br J Pharmacol Date: 2017-06-10 Impact factor: 8.739