Involvement of GPR43 Receptor in Effect of on Murine Steroid Resistant Chronic Obstructive Pulmonary Disease: Relevance to Pro-Inflammatory Mediators and Oxidative Stress in Human Macrophages.

BACKGROUND

Cytokine storm and oxidative stress are present in chronic obstructive pulmonary disease (COPD). Individuals with COPD present high levels of NF-κB-associated cytokines and pro-oxidant agents as well as low levels of Nrf2-associated antioxidants. This condition creates a steroid-resistant inflammatory microenvironment. (Lr) is a known anti-cytokine in lung diseases; however, the effect of Lr on lung inflammation and oxidative stress in steroid-resistant COPD mice remains unknown.

OBJECTIVE

Thus, we investigated the Lr effect on lung inflammation and oxidative stress in mice and macrophages exposed to cigarette smoke extract (CSE) and unresponsive to steroids.

METHODS

Mice and macrophages received dexamethasone or GLPG-094 (a GPR43 inhibitor), and only the macrophages received butyrate (but), all treatments being given before CSE. Lung inflammation was evaluated from the leukocyte population, airway remodeling, cytokines, and NF-κB. Oxidative stress disturbance was measured from ROS, 8-isoprostane, NADPH oxidase, TBARS, SOD, catalase, HO-1, and Nrf2.

RESULTS

Lr attenuated cellularity, mucus, collagen, cytokines, ROS, 8-isoprostane, NADPH oxidase, and TBARS. Otherwise, SOD, catalase, HO-1, and Nrf2 were upregulated in Lr-treated COPD mice. Anti-cytokine and antioxidant effects of butyrate also occurred in CSE-exposed macrophages. GLPG-094 rendered Lr and butyrate less effective.

CONCLUSIONS

Lr attenuates lung inflammation and oxidative stress in COPD mice, suggesting the presence of a GPR43 receptor-dependent mechanism also found in macrophages.