Research

Serine/threonine kinase-protein kinase B and extracellular signal-regulated kinase regulate ventilator-induced pulmonary fibrosis after bleomycin-induced acute lung injury: a prospective, controlled animal experiment

Li-Fu Li^1,2,3 , Shuen-Kuei Liao⁴ , Chung-Chi Huang^1,2,3 , Ming-Jui Hung^4,5 and Deborah A Quinn^6,7,8

¹Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan

²Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan

³Department of Respiratory Therapy, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan

⁴Graduate Institute of Clinical Medical Sciences, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan

⁵Cardiology Section, Department of Medicine, Chang Gung Memorial Hospital at Keelung, 222 Maijin Road, Keelung 204, Taiwan

⁶Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 148, Boston, MA 02114, USA

⁷Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA

⁸Novartis Institute of Biomedical Research, 250 Massachusetts Avenue, Cambridge 02140, MA, USA

author email corresponding author email

Critical Care 2008, 12:R103doi:10.1186/cc6983

Published:	9 August 2008

Abstract

Introduction

Lung fibrosis, reduced lung compliance, and severe hypoxemia found in patients with acute lung injury often result in a need for the support of mechanical ventilation. High-tidal-volume mechanical ventilation can increase lung damage and fibrogeneic activity but the mechanisms regulating the interaction between high tidal volume and lung fibrosis are unclear. We hypothesized that high-tidal-volume ventilation increased pulmonary fibrosis in acute lung injury via the serine/threonine kinase-protein kinase B (Akt) and mitogen-activated protein kinase pathways.

Methods

After 5 days of bleomycin administration to simulate acute lung injury, male C57BL/6 mice, weighing 20 to 25 g, were exposed to either high-tidal-volume mechanical ventilation (30 ml/kg) or low-tidal-volume mechanical ventilation (6 ml/kg) with room air for 1 to 5 hours.

Results

High-tidal-volume ventilation induced type I and type III procollagen mRNA expression, microvascular permeability, hydroxyproline content, Masson's trichrome staining, S100A4/fibroblast specific protein-1 staining, activation of Akt and extracellular signal-regulated kinase (ERK) 1/2, and production of macrophage inflammatory protein-2 and 10 kDa IFNγ-inducible protein in a dose-dependent manner. High-tidal-volume ventilation-induced lung fibrosis was attenuated in Akt-deficient mice and in mice with pharmacologic inhibition of ERK1/2 activity by PD98059.

Conclusion

We conclude that high-tidal-volume ventilation-induced microvascular permeability, lung fibrosis, and chemokine production were dependent, in part, on activation of the Akt and ERK1/2 pathways.