Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340).
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.
Foda
H D
HD
Department of Medicine and Research, Veteran's Affairs Medical Center, Northport, New York, USA. hfoda@mail.som.sunysb.edu
Rollo
E E
EE
Drews
M
M
Conner
C
C
Appelt
K
K
Shalinsky
D R
DR
Zucker
S
S
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001469:Barotrauma / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D051926:Basigin; D002199:Capillary Permeability; D017077:Culture Media, Conditioned; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D007274:Injections, Intraperitoneal; D008168:Lung / Q000201:enzymology; D055370:Lung Injury; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D023421:Models, Animal; D009930:Organic Chemicals; D011175:Positive-Pressure Respiration / Q000009:adverse effects*; D011292:Premedication; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000517:prevention & control; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D012122:Ventilators, Mechanical
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D009930:Organic Chemicals; D014409:Tumor Necrosis Factor-alpha; C113282:prinomastat; D051926:Basigin; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein