Up-regulation of trypsin and mesenchymal MMP-8 during development of hyperoxic lung injury in the rat.
Acute lung injury is marked by damage to alveolar-capillary barrier. High pulmonary levels of matrix-degrading serine proteinase trypsin and matrix metalloproteinases (MMP)-2, -8, and -9 have been shown in preterm infants with respiratory distress syndrome (RDS). We studied expression of trypsin and MMP-2, -8, and -9 in rats exposed to >95% oxygen for 24, 48, or 60 h. As demonstrated by zymography and Western immunoblotting, levels of trypsin and MMP-2, -8, and -9 in bronchoalveolar lavage fluid (BALF) sharply increased after 48 h of hyperoxia relative to normoxia controls. This coincided with increase in alveolar-capillary permeability, as indicated by increased protein concentration in BALF. Both neutrophil-derived 80-kD and mesenchymal cell-derived 60-kD MMP-8 isoforms were detected in BALF. Of them, mesenchymal-type MMP-8 predominated. In immunohistochemistry, alveolar epithelium showed strong trypsin expression at 48 and 60 h of hyperoxia, whereas it was predominantly negative in controls. MMP-8 was mostly expressed in macrophages. Marked up-regulation of trypsin and MMP-8 early during hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury and may therefore be potential targets for therapy of lung injury.
Cederqvist
Katariina
K
Department of Pediatrics, Helsinki University Central Hospital and University of Helsinki, FIN-00290 Helsinki, Finland. katariina.cederqvist@helsinki.fi
Janer
Joakim
J
Tervahartiala
Taina
T
Sorsa
Timo
T
Haglund
Caj
C
Salmenkivi
Kaisa
K
Stenman
Ulf-Håkan
UH
Andersson
Sture
S
D000818:Animals; D005260:Female; D018496:Hyperoxia / Q000150:complications / Q000201:enzymology*; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D020784:Matrix Metalloproteinase 8 / Q000032:analysis / Q000378:metabolism*; D010100:Oxygen / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014357:Trypsin / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation
D014357:Trypsin; D020784:Matrix Metalloproteinase 8; D010100:Oxygen