Chronic Hypoxia Induces Constitutive p38 Mitogen-activated Protein Kinase Activity That Correlates with Enhanced Cellular Proliferation in Fibroblasts from Rat Pulmonary But Not Systemic Arteries

• Published in: American journal of respiratory and critical care medicine Vol. 164; no. 2; pp. 282 - 289
• Main Authors: WELSH, DAVID J, PEACOCK, ANDREW J, MacLEAN, MARGARET, HARNETT, MARGARET
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.07.2001; American Lung Association
• Subjects: Animals; Biological and medical sciences; Cell Division; Chronic Disease; Fibroblasts - cytology; Fibroblasts - enzymology; Hypoxia - enzymology; Male; Medical sciences; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Pneumology; Pulmonary Artery; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Wistar; Cell proliferation; Oxygen; Pathophysiology; Rat; Respiratory disease; Enzyme; Pathogenesis; Transferases; Acute; Rodentia; Cardiovascular disease; Pulmonary artery; Pulmonary hypertension; Vascular remodeling; Vertebrata; Chronic; Mammalia; Protein kinase; Animal; Aorta; Hypoxia; Vascular wall; Fibroblast; Comparative study
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.164.2.2008054

Pulmonary hypertension occurs commonly in patients with chronic hypoxic lung disease and is characterized by the remodeling of the pulmonary artery walls. The molecular mechanisms underlying such remodeling are unknown but we have recently shown that the stress-activated (Jnk and p38) mitogen-activated protein (MAP) kinases are activated in pulmonary artery fibroblasts following acute hypoxia. We now show that Erk and p38 MAP kinases are constitutively activated in fibroblasts derived from the remodeled pulmonary, but not the systemic circulation from rats exposed to chronically hypoxic conditions. Moreover, we find that such fibroblasts show sustained enhanced proliferative capacities relative to pulmonary artery fibroblasts derived from normoxic rats or to aortic fibroblasts from either normoxic or hypoxic rats. Finally, abrogation of p38, but not Erk MAP kinase activity by use of specific inhibitors, prevents the enhanced proliferative capacity exhibited by pulmonary artery fibroblasts. Taken together, these data suggest that enhanced p38 MAP kinase activity provides a molecular mechanism to explain the proliferation of pulmonary artery fibroblasts required for remodeling of the pulmonary vasculature.