Alternative Roles of STAT3 and MAPK Signaling Pathways in the MMPs Activation and Progression of Lung Injury Induced by Cigarette Smoke Exposure in ACE2 Knockout Mice

Abstract

Inflammation-mediated abnormalities in the renin-angiotensin system (RAS) and expression of matrix metalloproteinases (MMPs) are implicated in the pathogenesis of lung injury. Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue that displays antagonist effects on ACE/angiotensin II (Ang II) axis, could also play a protective role against lung diseases. However, the relationship between ACE2 and MMPs activation in lung injury is still largely unclear. The purpose of this study is to investigate whether MMPs activity could be affected by ACE2 and which ACE2 derived signaling pathways could be also involved via using a mouse model with lung injury induced by cigarette smoke (CS) exposure for 1 to 3 weeks. Wild-type (WT; C57BL/6) and ACE2 KO mice (ACE2-/-) were utilized to study CS-induced lung injury. Increases in the resting respiratory rate (RRR), pulmonary immunokines, leukocyte infiltration and bronchial hyperplasia were observed in the CS-exposed mice. Compared to WT mice, more serious physiopathological changes were found in ACE2-/- mice in the first week of CS exposure. CS exposure increased pulmonary ACE and ACE2 activities in WT mice, and significantly increased ACE in ACE2-/- mice. Furthermore, the activity of pulmonary MMPs was decreased in CS-exposed WT mice, whereas this activity was increased in ACE2-/- mice. CS exposure increased the pulmonary p-p38, p-JNK and p-ERK1/2 level in all mice. In ACE2-/- mice, a significant increase p-STAT3 signaling was detected; however, no effect was observed on the p-STAT3 level in WT mice. Our results support the hypothesis that ACE2 deficiency influences MMPs activation and STAT3 phosphorylation signaling to promote more pulmonary inflammation in the development of lung injury.

ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19

“…To our knowledge, our study is the first to demonstrate increased ACE-2 expression in the airways of current (but not former) smokers and those with COPD. These results are also consistent with previous observations in small animals wherein smoke exposure has been shown to upregulate both the expression and activity of ACE-2 in the airways [19,20]. While the upregulation of ACE-2 may be useful in protecting the host against acute lung injury, chronically, this may predispose individuals to an increased risk of coronavirus infections, which use this receptor to gain entrance into epithelial cells.…”

Clinical characteristics and diagnostic challenges of pediatric COVID-19: A systematic review and meta-analysis

“…30 There is one hypothesis that smoking increases ACE2 expression and thus enhances coronavirus entry into pulmonary epithelial cells. 31 Undoubtedly, smoking is more prevalent among adults than among children. Nonetheless, some controversies exist.…”

Nicotine and the renin-angiotensin system

“…In addition, losartan administration in vivo reduced ANG II level in the lung, restored ACE2 expression, and ameliorated pulmonary vascular remodeling and smoke-induced increase in right ventricular systolic pressure (60,148). Koka et al (81) showed that ANG II downregulates ACE2 via AT 1 R-mediated extracellular signal-regulated kinase (ERK)/p38 MAPK signaling pathways; thus the decreased ACE2 expression by chronic cigarette smoke exposure could be mediated by a mechanism dependent on ANG II and AT 1 R. Cigarette smoke exposure in mice also increases ACE expression in the lung, and this upregulation was greater in ACE2 knockout mice compared with the wild-type controls (69). In addition, ACE2 knockout mice exhibited increased inflammation with activation of MMPs and signal transducer and activator of transcription 3 following cigarette smoke exposure (69).…”