THE ANGIOTENSIN II TYPE 1 RECEPTOR MEDIATES BRONCHOPULMONARY INFLAMMATION AND THE AIRWAY REMODELING PROCESS INDUCED BY THE SARS-COV-2 SPIKE PROTEIN IN ASTHMATIC MICE

Asthma is a chronic inflammatory disease, and it has been demonstrated that asthmatic patients have a low-grade SARS-CoV-2 infection. The renin-angiotensin system (RAS) participates in airway inflammation and remodeling. We evaluated whether the AT1 receptor is involved in the bronchopulmonary response induced by the spike protein (Sp) in asthmatic mice. Male BALB/c mice were sensitized intraperitoneally with ovalbumin (OVA; 50 μg/animal) on days 0 and 7 and challenged intranasally with OVA (25 μg/animal) on day 14, followed by Sp (10 μg/animal) on day 15, with or without losartan (LOS; 30 mg/kg/day). After 48 h, inflammatory cells in bronchoalveolar lavage (BAL) and lungs, airway remodeling (AR), mucus production (M), fibrosis, and ACE2 activity were evaluated. OVA increased total cells, eosinophils (EO), and mononuclear cells (Mono) in BAL (p≤0.0001), and EO in lungs (p≤0.0001), as well as AR, M, and peribronchiolar (Pb) and perivascular (Pv) fibrosis. Sp increased EO (p≤0.001), neutrophils (NE) (p≤0.0001), and Mono in BAL and NE in lungs (p≤0.0001), with bronchial wall thickening, inflammation, and Pv fibrosis but no detectable M. OVA+Sp did not further increase EO, NE, or Mono in BAL compared with OVA, but it induced pulmonary inflammatory infiltration, AR without M, and Pb fibrosis. OVA+LOS reduced OVA-induced total cells, EO (p≤0.001), and Mono recruitment (p≤0.001) in BAL and reduced pulmonary inflammatory infiltration, AR, and Pb and Pv fibrosis. Sp+LOS reduced Sp-induced total cells, EO and Mono recruitment in BAL and partially preserved pulmonary architecture. In OVA+LOS+Sp, LOS reduced NE in BAL (p≤0.05), partiwerey reversed AR, M was detected, and Pb and Pv fibrosis was not detected, but it did not reduce EO recruitment. ACE2 activity increased in OVA (p≤0.05) and was higher in OVA+LOS+Sp than in OVA+Sp (p≤0.0001). Overall, AT1 is an important modulator of OVA-induced asthma and plays a partial role in Sp-associated inflammation, AR and ACE2 regulation.