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CRITICAL CARE AND TRAUMA

Ventilator-Induced Lung Injury Is Associated with Neutrophil Infiltration, Macrophage Activation, and TGF-ß1 mRNA Upregulation in Rat Lungs

Hideaki Imanaka, MD^*, Motomu Shimaoka, MD^§, Nariaki Matsuura, MD, Masaji Nishimura, MD, Noriyuki Ohta, MD^§, and Hiroshi Kiyono, DDS, PhD^§

*Surgical Intensive Care Unit, National Cardiovascular Center; Intensive Care Unit, Osaka University Hospital; Department of Pathology, School of Allied Health Sciences, Osaka University; and §Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Address correspondence and reprint requests to Hideaki Imanaka, MD, Surgical Intensive Care Unit, National Cardiovascular Center, Fujishiro-dai, Suita, Osaka, Japan 565. Address e-mail to imanakah{at}hsp.ncvc.go.jp

Activated neutrophils contribute to the development of ventilator-induced lung injury (VILI) caused by high-pressure mechanical ventilation. However, exact cellular and molecular mechanisms have not been conclusively studied. Our investigation aimed to examine expression of adhesion molecules by both neutrophils and macrophages in lung lavage fluids of rats with VILI. Further, involvement of proinflammatory (tumor necrosis factor-) and profibrogenetic (transforming growth factor-ß1) mediators was analyzed at mRNA level in lung tissue. Wistar rats were ventilated by high pressure (45 cm H₂O of peak inspiratory pressure, n = 23) or low pressure (7 cm H₂O, n = 13) with 0 positive end-expiratory pressure. After 40 min of comparative ventilation, lung lavage was performed in 20 rats from the experimental group and 10 from the control for immunofluorescence analysis with anti-Mac-1 and anti-ICAM-1 monoclonal antibodies. The lung tissues from remaining rats were subjected to pathological and reverse transcription-polymerase chain reaction examinations. Although there was no significant change of PaO₂ in the low-pressure group, PaO₂ was decreased in the high-pressure group. The high-pressure group also had greater neutrophil infiltration into alveolar spaces, upregulation of CD54 and CD11b on alveolar macrophages, and more transforming growth factor-ß1 mRNA in lung tissues. Tumor necrosis factor- was not involved in the pathogenesis of the severe VILI observed. Histologic findings also demonstrated more infiltrating neutrophils, destructive change of the alveolar wall, and deposition of matrix in the high-pressure group. These results suggest that a series of proinflammatory reactions and profibrogenetic process may be involved in the course of VILI.

Implications: High-pressure ventilation demonstrated, in the early phase, not only proinflammatory processes, including neutrophil infiltration and adhesion molecules upregulation on macrophages, but profibriogenetic processes, including transforming growth factor-ß1 mRNA expression in the lung tissue. These immunological alterations may be involved in the progress of ventilator-induced lung injury.

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