Metformin Ameliorates Inflammation and Airway Remodeling of Experimental Allergic Asthma in Mice by Restoring AMPKα Activity.

Wenxian Ma,Xinpeng Han,Haiqin Guo,Qiaoyan Jin,Shemin Lu,Changgui Wu,Lingbin Xu

doi:10.3389/fphar.2022.780148

Abstract

Metformin has been involved in modulating inflammatory state and inhibiting cell proliferation and angiogenesis. This study aimed to determine whether metformin alleviates airway inflammation and remodeling of experimental allergic asthma and elucidate the underlying mechanism. We sensitized and challenged mice with ovalbumin (OVA) to induce allergic asthma. During the challenge period, metformin was administered by intraperitoneal injection. By histopathological and immunohistochemical analyses, metformin-treated mice showed a significant alleviation in airway inflammation, and in the parameters of airway remodeling including goblet cell hyperplasia, collagen deposition and airway smooth muscle hypertrophy compared to those in the OVA-challenged mice. We also observed elevated levels of multiple cytokines (IL-4, IL-5, IL-13, TNF-α, TGF-β1 and MMP-9) in the bronchoalveolar lavage fluid, OVA-specific IgE in the serum and angiogenesis-related factors (VEGF, SDF-1 and CXCR4) in the plasma from asthmatic mice, while metformin reduced all these parameters. Additionally, the activity of 5′-adenosine monophosphate-activated protein kinase a (AMPKα) in the lungs from OVA-challenged mice was remarkably lower than control ones, while after metformin treatment, the ratio of p-AMPKα to AMPKα was upregulated and new blood vessels in the sub-epithelial area as evidenced by CD31 staining were effectively suppressed. These results indicate that metformin ameliorates airway inflammation and remodeling in an OVA-induced chronic asthmatic model and its protective role could be associated with the restoration of AMPKα activity and decreased asthma-related angiogenesis.

Highlights

Asthma is considered as a heterogeneous disease with two typical features, airway chronic inflammation and remodeling, and affects around 334 million people worldwide (Papi et al, 2018)
To further evaluate the effect of the metformin on airway remodeling in the OVA-sensitized/challenged mice, we conducted histopathological staining with Periodic Acid-Schiff (PAS), Masson’s trichrome and immunohistochemistry (IHC) to evaluate mucus production, collagen deposition, airway smooth muscle (ASM) proliferation and airway fibrosis respectively
Our animal experiment demonstrated that metformin significantly reduced pathologic changes in the lungs due to inflammatory cells recruitment, inflammatory mediator spillover, goblet cell hyperplasia, ASM hypertrophy, subepithelial fibrosis and neovascularization

Summary

Introduction

Asthma is considered as a heterogeneous disease with two typical features, airway chronic inflammation and remodeling, and affects around 334 million people worldwide (Papi et al, 2018). Airway inflammation in allergic asthma is mainly characterized by T helper 2 (Th2) cells hyper-activation in response to allergens, followed by infiltration and activation of multiple inflammatory cells with the secretion of inflammatory cytokines (Boonpiyathad et al, 2019). Such a long-lasting inflammatory state could result in structural changes termed remodeling (Guida and Riccio, 2019). VEGF and lung-homing of endothelial progenitor cells (EPCs) driven by stromal cell derived factor-1 (SDF-1) binding CXCR4 receptor are crucial to bronchial vascularity in asthma (Imaoka et al, 2011; Janssens et al, 2018; Laddha and Kulkarni, 2019). Novel approaches for asthma treatment should attempt to target both chronic inflammation and remodeling of asthmatic airways

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