title: Metalloproteinase inhibition reduces lung injury and improves survival after cecal ligation and puncture in rats.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, SUNY Upsate Medical University, Syracuse, NY 13210, USA. steinbja@uptate.edu
authors.forename: Jay
authors.initials: J
authors.lastname: Steinberg
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Halter
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Schiller
authors.forename: Monica
authors.initials: M
authors.lastname: Dasilva
authors.forename: Steve
authors.initials: S
authors.lastname: Landas
authors.forename: Louis A
authors.initials: LA
authors.lastname: Gatto
authors.forename: Paivi
authors.initials: P
authors.lastname: Maisi
authors.forename: Timo
authors.initials: T
authors.lastname: Sorsa
authors.forename: Minna
authors.initials: M
authors.lastname: Rajamaki
authors.forename: Hsi-Ming
authors.initials: HM
authors.lastname: Lee
authors.forename: Gary F
authors.initials: GF
authors.lastname: Nieman
mesh_terms: D000818:Animals; D002432:Cecum; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D008026:Ligation; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011677:Punctures; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000517:prevention & control; D018805:Sepsis / Q000150:complications* / Q000209:etiology; D013752:Tetracycline / Q000627:therapeutic use; D013754:Tetracyclines
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D013754:Tetracyclines; C117155:tetracycline CMT-3; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D013752:Tetracycline