BIPHASIC EFFECTS OF SELECTIVE INHIBITION OF TRANSFORMING GROWTH FACTOR β1 ACTIVIN RECEPTOR-LIKE KINASE ON LPS-INDUCED LUNG INJURY

The present study was designed to find out whether SB431542, an inhibitor of transforming growth factor beta 1 activin receptor-like kinase, could protect the lung from LPS-induced injury. Inflammatory lung injury model was induced by intratracheal administration of LPS. C57BL/6 mice were randomly divided into the sham control group (S group), the LPS stimulation group (L group), the LPS + early SB431542 treatment group (le group), and the LPS + delayed SB431542 treatment group (Id group). SB431542 was admitted intraperitoneally on study days 1, 2, and 3 to the mice in le group, whereas those in Id group received the same dose of SB431542 on study days 4, 5, and 6. Pulmonary TNF-alpha and IL-1 beta mRNA expressions were tested. Pathological evaluations of pulmonary alveolitis and collagen deposition and fibrosis were performed on study days 7 and 28, along with the determination of pulmonary hydroxyproline, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 1 on study day 28. As a result, LPS stimulation resulted in significant increases of the pulmonary TNF-alpha and IL-1 beta mRNA expressions as well as pathological scores for alveolitis on day 7 and increased collagen deposition, hydroxyproline content, and pathological scores for fibrosis on day 28, with a decrease of matrix metalloproteinase 9 activity. Those parameters were further aggravated in the le group whereas relieved significantly in the Id group. These data suggest that SB431542 therapy for inflammatory lung injury could be harmful if performed during early-phase inflammatory response. However, the therapy would prevent lung from inflammatory injury and fibrosis if it was initiated late.