Rho-kinase inhibitor prevents bleomycin-induced injury in neonatal rats independent of effects on lung inflammation

Alvin H Lee; Rupinder Dhaliwal; Crystal Kantores; Julijana Ivanovska; Kiran Gosal; Patrick J McNamara; Michelle Letarte; Robert P Jankov

doi:10.1165/rcmb.2013-0131OC

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Rho-kinase inhibitor prevents bleomycin-induced injury in neonatal rats independent of effects on lung inflammation

Journal article

Peer reviewed

Rho-kinase inhibitor prevents bleomycin-induced injury in neonatal rats independent of effects on lung inflammation

Alvin H Lee, Rupinder Dhaliwal, Crystal Kantores, Julijana Ivanovska, Kiran Gosal, Patrick J McNamara, Michelle Letarte and Robert P Jankov

American journal of respiratory cell and molecular biology, Vol.50(1), pp.61-73

01/2014

DOI: 10.1165/rcmb.2013-0131OC

PMID: 23947621

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Abstract

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.

Tumor Necrosis Factor-alpha - metabolism

Pneumonia - pathology

Hypertension, Pulmonary - chemically induced

Hypertension, Pulmonary - prevention & control

rho-Associated Kinases - antagonists & inhibitors

Hypertrophy, Right Ventricular - drug therapy

Macrophages - diagnostic imaging

Pulmonary Artery - metabolism

rho-Associated Kinases - metabolism

Lung Injury - metabolism

Vascular Resistance - drug effects

Lung Injury - prevention & control

Lung - metabolism

Hypertrophy, Right Ventricular - metabolism

Neutrophils - metabolism

Neutrophils - pathology

Amides - pharmacology

Animals, Newborn

Lung - pathology

Neutrophils - drug effects

Enzyme Inhibitors - pharmacology

Rats

Hypertension, Pulmonary - metabolism

Bleomycin - adverse effects

Pulmonary Artery - drug effects

Down-Regulation - drug effects

Rats, Sprague-Dawley

Radiography

Macrophages - metabolism

Animals

Neovascularization, Pathologic - drug therapy

Lung - drug effects

Macrophages - drug effects

Chemokines - metabolism

Neovascularization, Pathologic - metabolism

Pneumonia - diagnostic imaging

Pyridines - pharmacology

Thrombospondin 1 - metabolism

Lung Injury - chemically induced

Pneumonia - metabolism

Hypertension, Pulmonary - pathology

Pulmonary Artery - pathology

Details

Title: Subtitle: Rho-kinase inhibitor prevents bleomycin-induced injury in neonatal rats independent of effects on lung inflammation
Creators: Alvin H Lee - 1 Physiology and Experimental Medicine and
Rupinder Dhaliwal
Crystal Kantores
Julijana Ivanovska
Kiran Gosal
Patrick J McNamara
Michelle Letarte
Robert P Jankov
Resource Type: Journal article
Publication Details: American journal of respiratory cell and molecular biology, Vol.50(1), pp.61-73
DOI: 10.1165/rcmb.2013-0131OC
PMID: 23947621
ISSN: 1044-1549
eISSN: 1535-4989
Grant note: Canadian Institutes of Health Research
Language: English
Date published: 01/2014
Academic Unit: Stead Family Department of Pediatrics; Neonatology; Internal Medicine
Record Identifier: 9984093332002771

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31 Times Cited - Web of Science