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ORIGINAL RESEARCH ARTICLE

Activated Protein C Protection from Lung Inflammation in Endotoxin-Induced Injury

Federica Pirrone^*,1, Silvia M. Mazzola^*, Camilla Pastore^*, Saverio Paltrinieri, Giuseppe Sironi, Pietro Riccaboni, Manuela Viola, Alberto Passi, Maria G. Clement^* and Mariangela Albertini^*

^* Department of Animal Pathology, Hygiene and Veterinary Public Health, Section of Biochemistry and Physiology, Faculty of Veterinary Medicine, University of Milan, Milan, Italy; Section of General Pathology and Parasitology, Faculty of Veterinary Medicine, University of Milan, Milan, Italy; and Department of Experimental and Clinical Biomedical Sciences, University of Insubria, Varese, Italy

To whom requests for reprints should be addressed at ¹ Department of Animal Pathology, Hygiene and Veterinary Public Health, Section of Biochemistry and Physiology, Faculty of Veterinary Medicine, University of Milan, Via Celoria, 10, 20133 Milan, Italy. E-mail: federica.pirrone{at}unimi.it

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 µ g/kg/hr), rhAPC (24 µ 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-1β 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.

Key Words: activated protein C • sepsis • acute lung injury • matrix metalloproteinases • swine