Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury.
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 (VT); 2) high tidal volume (HVT), 30 ml/kg of VT; 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.
Kim
Je Hyeong
JH
Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University, Seoul, and Institute of Human Genomic Study, Ansan Hospital, Korea.
Suk
Min Hyun
MH
Yoon
Dae Wui
DW
Lee
Seung Heon
SH
Hur
Gyu Young
GY
Jung
Ki Hwan
KH
Jeong
Hae Cheol
HC
Lee
Sung Yong
SY
Lee
Sang Yeub
SY
Suh
In Bum
IB
Shin
Chol
C
Shim
Jae Jeong
JJ
In
Kwang Ho
KH
Yoo
Se Hwa
SH
Kang
Kyung Ho
KH
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020556:Neutrophil Infiltration / Q000187:drug effects; D009929:Organ Size; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013194:Staining and Labeling; D013754:Tetracyclines / Q000494:pharmacology; D013990:Tidal Volume; D012122:Ventilators, Mechanical / Q000009:adverse effects*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013754:Tetracyclines; C117155:tetracycline CMT-3; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9