FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

Ying Liu,Jiawei Xu,Jiping Zhao,Liang Dong,Minfang Zou,Xiaofei Liu,Yun Pan,Jinxiang Wu,Tian Liu,Junfei Wang,Siyuan Huang,Lili Cao

doi:10.1186/s12890-021-01409-6

Abstract

BackgroundCigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling.MethodsSerum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed.ResultsBoth FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice.ConclusionsFSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

Highlights

Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD)
Follistatin-like protein 1 (FSTL1) expression and autophagy activation were elevated in COPD patients Our previous study has shown that FSTL1 may promote epithelial-mesenchymal transition (EMT) and airway remodeling in asthma by activating autophagy
We found increased circulating FSTL1 in the serum of COPD patients compared with control subjects (Fig. 1a)

Summary

Introduction

Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. Chronic obstructive pulmonary disease(COPD), one of the life-threatening respiratory system disorders, is projected to become the third most common cause of death worldwide by 2030 [1,2,3,4]. COPD is characterized by a sustained airflow limitation and emphysema associated with airway remodeling and inflammation [6]. Most studies showed that cigarette smoke was the major cause of pathogenesis and progression of COPD, which resulted in tremendous intractable inflammation and oxidative burden [8]. The underlying mechanisms of COPD induced by cigarette smoke are complex and not fully understood [9]. There are no accurate therapies that can effectively retard or reverse disease progression

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