Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury

1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University, Seoul; 2 Department of Nursing, College of Medicine, Pochon CHA University, Pochon; 3 Institute of Human Genomic Study, Ansan Hospital, Korea University Medical Center, Ansan; and 4 Department of Clinical Pathology, College of Medicine, Kangwon National University, Chuncheon, Korea Submitted 23 June 2005 ; accepted in final form 27 April 2006 Neutrophils are considered to play a central role in ventilator-induced lung injury (VILI). However, the pulmonary consequences of neutrophil accumulation have not been fully elucidated. Matrix metalloproteinase-9 (MMP-9) had been postulated to participate in neutrophil transmigration. The purpose of this study was to investigate the role of MMP-9 in the neutrophilic inflammation of VILI. Male Sprague-Dawley rats were divided into three groups: 1 ) low tidal volume (LVT), 7 ml/kg of tidal volume (V T ); 2 ) high tidal volume (HVT), 30 ml/kg of V T ; and 3 ) HVT with MMP inhibitor (HVT+MMPI). As a MMPI, CMT-3 was administered daily from 3 days before mechanical ventilation. Degree of VILI was assessed by wet-to-dry weight ratio and acute lung injury (ALI) scores. Neutrophilic inflammation was determined from the neutrophil count in the lung tissue and myeloperoxidase (MPO) activity in the bronchoalveolar lavage fluid (BALF). MMP-9 expression and activity were examined by immunohistochemical staining and gelatinase zymography, respectively. The wet-to-dry weight ratio, ALI score, neutrophil infiltration, and MPO activity were increased significantly in the HVT group. However, in the HVT+MMPI group, pretreatment with MMPI decreased significantly the degree of VILI, as well as neutrophil infiltration and MPO activity. These changes correlated significantly with MMP-9 immunoreactivity and MMP-9 activity. Most outcomes were significantly worse in the HVT+MMPI group compared with the LVT group. In conclusion, VILI mediated by neutrophilic inflammation is closely related to MMP-9 expression and activity. The inhibition of MMP-9 protects against the development of VILI through the downregulation of neutrophil-mediated inflammation. metalloproteinase inhibitor; neutrophil; mechanical ventilators Address for reprint requests and other correspondence: K. H. Kang, Division of Pulmonology and Critical Care Medicine, Dept. of Internal Medicine, Korea Univ. Guro Hospital #97, Gurodong-Gil, Guro-Gu, Seoul, 152-70