ASK1 inhibition reduced elastase-induced pulmonary emphysema in mice

Introduction

Pulmonary emphysema, a progressive lung disease, is a form of Chronic Obstructive Pulmonary Disease (COPD). There is no effective treatment for COPD, a condition that is the third cause of death in the world. ASK1, apoptosis signal-regulating kinase 1, has been demonstrated a key inflammatory regulator in lung experimental model of diseases. Here we investigated experimental treatment with selonsertib, an ASK1 inhibitor, in elastase-induced emphysema in mice.

Methods

Male C57BL/6 mice received 0.5U of elastase i.t. and after 7 days the treatment with selonsertib at the doses of 0.2, 0.5 and 2.0 mg/kg i.n. was made. On the 21st day mice were euthanized, bronchoalveolar lavage was performed and the lungs were removed for histological and biochemical studies.

Results

Selonsertib treatment was able to prevent emphysema at the higher dose observed by histological images and morphometrical/stereological counts. Inflammatory cells in lungs were higher in emphysematous mice but reduced only in the 2mg selonsertib treatment group. ROS production reduced in the 2mg selonsertib treatment group when compared to the emphysematous group. Cytokines levels (CX3CL1, CCL2, IL-6 and IL-1beta) increased in the emphysematous group but reduced in the selonsertib treated groups (mainly 0.5 and 2 mg). Immunostaining for pASK1 in lung samples were strongly positive in emphysematous group but reduced in selonsertib treated group (2mg only), as well as caspase 3 and neutrophil elastase.

Conclusion

Taken together these results indicates that selonsertib is an effective drug for prevent emphysema lesions in mice by improving histology, reducing inflammation and oxidative stress and attenuating apoptosis. These findings indicate ASK1 as a potential target for COPD treatment.