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 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.
Vural
K M
KM
Department of Cardiothoracic Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, USA. kvural@tr-net.net.tr
Liao
H
H
Oz
M C
MC
Pinsky
D J
DJ
D000704:Analysis of Variance; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004205:Cromolyn Sodium / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000032:analysis; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006634:Histamine H1 Antagonists / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000187:drug effects; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D007665:Ketotifen / Q000627:therapeutic use*; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D018927:Anti-Asthmatic Agents; D006634:Histamine H1 Antagonists; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D004205:Cromolyn Sodium; D007665:Ketotifen