Instillation of particulate matter 2.5 induced acute lung injury and attenuated the injury recovery in ACE2 knockout mice

Abstract

Inhaled particulate matter 2.5 (PM2.5) can cause lung injury by inducing serious inflammation in lung tissue. Renin-angiotensin system (RAS) is involved in the pathogenesis of inflammatory lung diseases and regulates inflammatory response. Angiotensin-converting enzyme II (ACE2), which is produced through the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II) axis, protects against lung disease. However, few studies have focused on the relationships between PM2.5 and ACE2. Therefore, we aimed to explore the role of ACE2 in PM2.5-induced acute lung injury (ALI). An animal model of PM2.5-induced ALI was established with wild type (C57BL/6, WT) and ACE2 gene knockout (ACE2 KO) mice. The mice were exposed to PM2.5 through intratracheal instillation once a day for 3 days (6.25 mg/kg/day) and then sacrificed at 2 days and 5 days after PM2.5 instillation. The results show that resting respiratory rate (RRR), levels of inflammatory cytokines, ACE and MMPs in the lungs of WT and ACE2 KO mice were significantly increased at 2 days postinstillation. At 5 days postinstillation, the PM2.5-induced ALI significantly recovered in the WT mice, but only partially recovered in the ACE2 KO mice. The results hint that PM2.5 could induce severe ALI through pulmonary inflammation, and the repair after acute PM2.5 postinstillation could be attenuated in the absence of ACE2. Additionally, our results show that PM2.5-induced ALI is associated with signaling p-ERK1/2 and p-STAT3 pathways and ACE2 knockdown could increase pulmonary p-STAT3 and p-ERK1/2 levels in the PM2.5-induced ALI.

Traffic-derived particulate matter and angiotensin-converting enzyme 2 expression in human airway epithelial cells

“…Although the effect of PM 10 on ACE2 expression in human airway cells has not previously been reported, our findings are compatible with an animal study that reported lung ACE2 protein expression in wild type mice increased by 1.3 fold at 2 days post intratracheal instillation of urban PM 2.5 (11). A putative protective effect of increased pulmonary ACE2 was suggested in this mouse model by complete recovery of PM-induced acute lung injury in wild type mice, and incomplete recovery in ACE2 knockout mice (11). We therefore speculate that increased ACE2 expression may, on one hand, be a beneficial response to PM exposure, but on the other hand presents a Trojan horse to the SARS-CoV-2 virus.…”

Air pollution by NO2 and PM2.5 explains COVID-19 infection severity by overexpression of angiotensin-converting enzyme 2 in respiratory cells: a review

“…These authors have reported it as a "double hit hypothesis" because both NO 2 and PM 2.5 are described as responsible for increasing the severity in respiratory and associated other diseases and COVID-19 in Italy. Similar study done in mice model indicates that PM 2.5 chronic exposure is highly responsible for upregulate angiotensin converting enzyme expression (Aztatzi-Aguilar et al 2015;Lin et al 2018). Therefore, the authors had concluded that patients who breathe polluted air that exceeds the normal limit of PM 2.5 are at the higher risk of experiencing the severity of COVID-19 once they get infected.…”

In Vitro and In Vivo Experimental Studies of PM2.5 on Disease Progression

“…Acute PM 2.5 exposure enhances pulmonary oxidative stress and inflammatory responses and deteriorates pulmonary impedance in mice [ 106 ]. C57BL/6 mice that were exposed to PM 2.5 demonstrated a significant inflammatory response via the elevation of MCP-1 and neutrophils in the lung tissue [ 107 ]. ACE2 knockdown will enhance inflammatory response, tissue remodeling and attenuate injury repair in PM 2.5 -induced acute lung injury via p-STAT3 and p-ERK1/2 signaling pathways [ 108 ].…”