p38 MAP kinase: essential role in hypoxia-mediated human pulmonary artery fibroblast proliferation

Heather J. Mortimer, Andrew J. Peacock, Alan Kirk, David J. Welsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Pulmonary arterial hypertension (PAH) is a disease that results in thickening of the vascular wall. Some of the most prominent changes are seen in the adventitia as a result of fibroblast proliferation and increased extracellular matrix deposition. Previous work from this laboratory using animal models has shown that pulmonary but not systemic artery fibroblasts proliferate to hypoxic exposure and that this response is dependent on activation of p38 mitogen-activated protein kinase (p38MAPK). In this study, we wished to determine whether human pulmonary artery fibroblasts (HPAFs) behaved similarly under conditions of acute hypoxic exposure (35 mmHg for 24 h). Fibroblast proliferation was assessed by [3H]thymidine uptake and protein assays performed using Western blotting techniques. HPAFs proliferated in response to acute hypoxic exposure, human systemic artery fibroblasts did not. This hypoxia-mediated proliferation was p38 MAPK dependent and could be blocked using a specific p38 MAPK inhibitor. Hypoxia-inducible factor-1 (HIF-1) expression was increased in hypoxic pulmonary but not systemic cells and could be partially abrogated with the p38 inhibitor. This work in man confirmed our previous findings in animals that significant differences exist between the pulmonary and systemic circulations in response to hypoxic exposure. This study highlights the importance of p38 MAPK and HIF-1 in hypoxia-mediated proliferation of pulmonary artery adventitial fibroblasts.

Original languageEnglish
Pages (from-to)718-725
Number of pages8
JournalPulmonary Pharmacology and Therapeutics
Volume20
Issue number6
Early online date8 Sep 2006
DOIs
Publication statusPublished - Dec 2007

Keywords

  • hypoxia
  • molecular biology
  • pulmonary hypertension
  • remodelling

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Biochemistry, medical
  • Pharmacology (medical)

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