P1 Inhibition of jak/stat3 signaling pathway by small molecule r548 prevents inflammation in experimental murine lung injury model
V. Karavana1, I. Smith2, G. Kanellis3, I. Sigala1, T. Kinsella2, S. Zakynthinos1
1George P. Livanos and Marianthi Simou Laboratories, Athens, Greece; 2Rigel Pharmaceuticals, Inc, South San Francisco, CA, USA; 3Evangelismos Hospital, Athens, Greece
Introduction: Aberrant inflammation is a hallmark of acute respiratory distress syndrome (ARDS) pathophysiology. JAK/STAT3 pathway is critical for macrophages and neutrophils activation and persistent inflammation. This study aims to investigate the therapeutic potential of inhibiting JAK1/3 activity using the small-molecule R548 inhibitor in LPS induce lung injury model.
Methods: Lung injury was induced in adult male C57BL/6 mice, by intratracheal LPS administration followed by post subcutaneous injection of R548 inhibitor R548 inhibitor, prodrug for the active compound, R507 (Rigel Pharmaceuticals Inc.). Mice sacrificed at 6 h and 24 h after LPS administration. Lung inflammation was examined by protein content, number and type of inflammatory cells in bronchoalveolar lavage fluid (BALF). Protein expression levels of JAK1, p-STAT3, ERK1/2 were analysed by Western blotting.
Results: LPS administration increased BALF cellularity, total protein content, and neutrophils cells number at both 6 h and 24 h. Elevated levels of JAK1, p-STAT3 and ERK1/2 protein expression were observed. In addition, post LPS treatment with the JAK 1/3 inhibitor significantly reduces BALF protein content (P < 0.05), total cells number (P < 0.01), neutrophils cells number (P < 0.01) as early as 6 h. Moreover, R548 treatment decreased JAK1 protein expression by 2 fold (P < 0.01) and p-STAT3 levels by 2.7 fold (P < 0.001) below the LPS group.
Conclusions: These data suggest the JAK/STAT3 signaling pathway plays a critical role in ARDS mediated lung inflammation and injury. Additional studies are warranted to further investigate JAK/STAT3 inhibition as a therapeutic treatment for this serious and life threatening disease.