Cigarette smoke-induced acute lung injury exacerbates non-typeable haemophilus influenzae-induced inflammation: Protective effect of andrographolide through Nrf2

Abstract

Background: Cigarette smoke (CS) is associated with many maladies, one of which is chronic obstructive pulmonary disease (COPD). As the disease progresses, patients may suffer from COPD exacerbation episodes which are commonly triggered by non-typeable Haemophilus influenza (NTHi) infection. The present study aimed to develop a CS-induced lung injury mouse model that increases inflammation induced by NTHi challenge, and investigate the protective effects of andrographolide, a bioactive molecule with anti-inflammatory and antioxidant properties isolated from the plant Andrographis paniculata . Methods: Female BALB/c mice, 6-8-week-old, were exposed to 4% 3R4F CS delivered using a peristaltic pump daily for 2 weeks to induce an acute lung injury model. Mice were then inoculated intratracheally with NTHi and sacrificed 48h after last bacteria challenge. Lung samples were collected for various analyses. Results: After 2 weeks of CS exposure and NTHi challenge, mice developed increased macrophage and neutrophil pulmonary infiltration, augmented cytokine levels and heightened oxidative damage. Andrographolide effectively reduced lung cellular infiltrates and decreased lung levels of TNF-a, IL-1β, CXCL1/KC, 8-OHdG, MMP-8 and MMP-9. The protective actions of andrographolide on CS increased NTHi-inflammation might be attributable to increased Nrf2 activation and Keap1 repressor function, resulting in enhanced gene expression of antioxidant enzymes including HO-1, GR, GPx-2, GCLM, and NQO1. Conclusion: Taken together, these findings strongly support a therapeutic potential for andrographolide in controlling COPD exacerbation.