Am. J. Respir. Cell Mol. Biol., Volume 25, Number 6, December, 2001 717-724

Ventilator-Induced Lung Injury Upregulates and Activates Gelatinases and EMMPRIN
Attenuation by the Synthetic Matrix Metalloproteinase Inhibitor, Prinomastat (AG3340)

Hussein D. Foda, Ellen E. Rollo, Michelle Drews, Cathleen Conner, Krzysztof Appelt, David R. Shalinsky, and Stanley Zucker

Department of Medicine and Research, Veteran's Affairs Medical Center, Northport, New York; The State University of New York at Stony Brook, Stony Brook, New York; and Agouron Pharmaceuticals, Inc., Department of Ophthalmology and Pharmacology Research, San Diego, California

Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.

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