Rho-kinase inhibitor prevents bleomycin-induced injury in neonatal rats independent of effects on lung inflammation.
Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation dominated by neutrophils and macrophages, inhibited distal airway and vascular development, and pulmonary hypertension, similar to human infants with severe bronchopulmonary dysplasia. Rho-kinase (ROCK) is known to mediate lung injury in adult animals via stimulatory effects on inflammation. We therefore hypothesized that inhibition of ROCK may ameliorate bleomycin-induced lung injury in the neonatal rat. Pups received daily intraperitoneal bleomycin or saline from Postnatal Days 1 through 14 with or without Y-27632, a ROCK inhibitor. Treatment with Y-27632 prevented bleomycin-induced pulmonary hypertension, as evidenced by normalized pulmonary vascular resistance, decreased right-ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. Bleomycin-induced changes in distal lung architecture, including septal thinning, inhibited alveolarization, and decreased numbers of peripheral arteries and capillaries, were partially or completely normalized by Y-27632. Treatment with Y-27632 or a CXCR2 antagonist, SB265610, also abrogated tissue neutrophil influx, while having no effect on macrophages. However, treatment with SB265610 did not prevent bleomycin-induced lung injury. Lung content of angiostatic thrombospondin-1 (TSP1) was increased significantly in the lungs of bleomycin-exposed animals, and was completely attenuated by treatment with Y-27632. Thrombin-stimulated TSP1 production by primary cultured rat pulmonary artery endothelial cells was also attenuated by Y-27632. Taken together, our findings suggest a preventive effect of Y-27632 on bleomycin-mediated injury by a mechanism unrelated to inflammatory cells. Our data suggest that improvements in lung morphology may have been related to indirect stimulatory effects on angiogenesis via down-regulation of TSP1.
1 Physiology and Experimental Medicine and.
Alvin H
AH
Lee
Rupinder
R
Dhaliwal
Crystal
C
Kantores
Julijana
J
Ivanovska
Kiran
K
Gosal
Patrick J
PJ
McNamara
Michelle
M
Letarte
Robert P
RP
Jankov
D000577:Amides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001761:Bleomycin / Q000009:adverse effects; D018925:Chemokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008264:Macrophages / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D019700:Thrombospondin 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D018925:Chemokines; D004791:Enzyme Inhibitors; D011725:Pyridines; D019700:Thrombospondin 1; D014409:Tumor Necrosis Factor-alpha; C582391:Thbs1 protein, rat; D001761:Bleomycin; C108830:Y 27632; D054460:rho-Associated Kinases