title: Prevention of ischemia/reperfusion-induced accumulation of matrix metalloproteinases in rat lung by preconditioning with nitric oxide.
abstract: BACKGROUND
  Pulmonary ischemia/reperfusion (I/R) injury is associated with degradation of structural proteins. Preconditioning by short-term inhalation of nitric oxide (NO) ameliorates some of the severe consequences of an I/R cycle. The aim of this study was to evaluate the effects of NO preconditioning on I/R-induced changes of matrix metalloproteinase (MMP) activity.
  
  
  METHODS
  Left lung in situ ischemia in rats was maintained for 1 h, followed by reperfusion for 30 min or 4 h. In the NO group, animals inhaled NO (15 ppm) for 10 min directly before ischemia. Changes of expression or activity of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and of neutrophil elastase (NE) in bronchoalveolar lavage fluid (BALF), lung tissue, and arterial plasma were analyzed by zymography and Western blotting. Western blotting was also used to detect tissue inhibitors of matrix proteases, the extracellular metalloproteinase inducer (EMMPRIN or CD147), and endostatin, a proteolytic collagen fragment.
  
  
  RESULTS
  Ischemia resulted in an increase of lavagable MMP activity (12.3-fold MMP-2, 8.1-fold MMP-7) at 30 min reperfusion. The activity of MMP-9 and NE in lung tissue progressively increased with time, whereas MMP-14 and MMP-2 were constant. Inhalation of NO prevented the early increase of MMP-2 and MMP-7 in BALF, but the level of MMP-9 and NE in tissue was not affected. The expression of tissue inhibitors of matrix proteases and EMMPRIN did not respond to any treatment. The release of endostatin proceeded in parallel to the level of MMPs in BALF. Significant correlations between MMP-9 and myeloperoxidase in lung tissue and between MMP-2/MMP-7 and plasma protein extravasation were found.
  
  
  CONCLUSIONS
  The early rise of MMP-2 and MMP-7 in BALF resulted from plasma protein extravasation, whereas MMP-9 and NE were imported into lung tissue via leukocyte invasion. The effect of NO inhalation on lavagable MMPs was secondary to the sealing of the permeability barrier.
authors.affiliation: Clinic for Cardiac Surgery, University Hospital Dresden, Dresden, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Waldow
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Witt
authors.forename: Anne
authors.initials: A
authors.lastname: Buzin
authors.forename: André
authors.initials: A
authors.lastname: Ulmer
authors.forename: Klaus
authors.initials: K
authors.lastname: Matschke
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018093:Gelatinases / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D019272:Leukocyte Elastase / Q000302:isolation & purification / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000302:isolation & purification / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control*; D016683:Supine Position; D013908:Thoracotomy / Q000009:adverse effects / Q000379:methods
chemical_list: D009569:Nitric Oxide; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D018093:Gelatinases; D020782:Matrix Metalloproteinases