Metalloproteinase inhibition reduces lung injury and improves survival after cecal ligation and puncture in rats

J Surg Res. 2003 May 15;111(2):185-95. doi: 10.1016/s0022-4804(03)00089-1.

Abstract

Background: Neutrophil activation with concomitant matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) release has been implicated in the development of sepsis-induced acute lung injury. We hypothesized that COL-3, a chemically modified tetracycline known to inhibit MMP-2 and MMP-9, would reduce lung injury and improve survival in rats following cecal ligation and puncture (CLP).

Methods: Sprague-Dawley rats were separated into five groups: 1) sham CLP+ carboxymethylcellulose (CMC; vehicle for COL-3, n = 6); 2) sham CLP + COL-3 (n = 6); 3) CLP + CMC (n = 10); 4) CLP + single-dose (SD) COL-3 administered concomitant with CLP (n = 9); and 5) CLP + multiple-dose (MD) COL-3 administered concomitant with CLP and at 24 h after CLP (n = 15). Rats were sacrificed at 168 h (7 days) or immediately after death, with survival defined as hours after CLP. Histological lung assessment was made based on neutrophil infiltration, alveolar wall thickening, and intraalveolar edema fluid. Lung MMP-2 and MMP-9 levels were assessed by immunohistochemistry. MMP-2 and MMP-9 levels were correlated with survival by simple regression analysis.

Results: The mortality of rats in the cecal ligation and puncture without treatment group (CLP + CMC) was 70% at 168 h. A single dose of COL-3 in the CLP + COL-3 (SD) group significantly reduced mortality to 54%. Furthermore, with a repeat dose of COL-3 at 24 h after CLP, mortality was significantly reduced to 33%. Pathologic lung changes seen histologically in the CLP + CMC group were significantly reduced by COL-3. A significant reduction in lung tissue levels of MMP-2 and MMP-9 was noted in both groups treated with COL-3. Reduction of MMP-2 and MMP-9 levels correlated with improved survival.

Conclusion: Inhibition of MMP-2 and MMP-9 by COL-3 in a clinically relevant model of sepsis-induced acute lung injury reduces pulmonary injury and improves survival in a dose-dependent fashion. Our results suggest that prophylactic treatment with COL-3 in high-risk patients may reduce the morbidity and mortality associated with sepsis-induced acute respiratory distress syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cecum
  • Chromatography, High Pressure Liquid
  • Disease Models, Animal
  • Enzyme Inhibitors / therapeutic use*
  • Ligation
  • Lung / enzymology
  • Lung / pathology
  • Lung Diseases / etiology
  • Lung Diseases / pathology
  • Lung Diseases / prevention & control*
  • Male
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / analysis
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Metalloendopeptidases / antagonists & inhibitors*
  • Punctures
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Distress Syndrome, Adult / etiology
  • Respiratory Distress Syndrome, Adult / prevention & control
  • Sepsis / complications*
  • Sepsis / etiology
  • Tetracycline / therapeutic use
  • Tetracyclines

Substances

  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Tetracyclines
  • tetracycline CMT-3
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Tetracycline