Activated protein C protection from lung inflammation in endotoxin-induced injury.
We studied the protection of recombinant human activated protein C (rhAPC) in endotoxin-induced lung inflammation and injury and whether this effect is correlated with modulation of lung matrix metalloproteinase (MMP) activity. We randomly assigned 12 Large White pigs to receive intravenous Escher-ichia coli lipopolysaccharide (LPS; 40 mu g/kg/hr), rhAPC (24 mu g/ kg/hr), or both. We monitored respiratory mechanics and function, cell counts, and cytokine concentrations in bron-choalveolar lavage fluid (BALF). Lung samples were collected for the zymography of MMP-2 and MMP-9 activities and for histology. In septic pigs, rhAPC decreased proMMP-9 release as well as MMP-9 activation, and increased proMMP-2 presence without any evident activation compared with specimens that were given LPS alone. In addition, lung injury in rhAPC-treated animals was significantly attenuated, as shown by higher respiratory compliance, delayed increase in tumor necrosis alfa and interleukin-1beta as well as neutrophil recruitment in the BALF, reduced lung edema, and histologic changes. In conclusion, rhAPC is beneficial in acute lung injury, and the protection may depend, at least in part, on modulation of MMP-2/9 activity.
Pirrone
Federica
F
Department of Animal Pathology, Hygiene and Veterinary Public Health, University of Milan, Via Celoria, 10, 20133 Milan, Italy. federica.pirrone@unimi.it
Mazzola
Silvia M
SM
Pastore
Camilla
C
Paltrinieri
Saverio
S
Sironi
Giuseppe
G
Riccaboni
Pietro
P
Viola
Manuela
M
Passi
Alberto
A
Clement
Maria G
MG
Albertini
Mariangela
M
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004926:Escherichia coli; D006801:Humans; D008070:Lipopolysaccharides; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011014:Pneumonia / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D020011:Protective Agents / Q000627:therapeutic use*; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012129:Respiratory Function Tests; D013552:Swine
D008070:Lipopolysaccharides; D020011:Protective Agents; D011486:Protein C; D011994:Recombinant Proteins; D020782:Matrix Metalloproteinases