Archive | 2021
Angiotensin (Ang-1-7) and Its Glycopeptide PNA5 Protect Against Overzealous Pulmonary Inflammation to Infectious and Non-Infectious Respiratory Insults
Abstract
RATIONALE: The peptide hormone angiotensin (Ang-(1-7)) has well-known anti-inflammatory protective effects, inhibiting production and expression of many cytokines and adhesion molecules that are associated with a cytokine storm. Recent reports suggest that ARDS appears to be a significant predictor of mortality and the COVID-19-induced cytokine storm is associated with increased morbidity and mortality. PNA5, a more stable, longer acting, and more brain penetrant glycopeptide analog of Ang-(1-7), has been developed to control inflammation. Our studies were developed to test if Ang-(1-7) and its glycopeptide PNA5 were protective in the lung against overzealous immune responses to infectious and non-infectious respiratory stimuli. METHODS: Wild type mice were treated with infectious or non-infectious agents: Mycoplasma pneumoniae (1x108, intranasal) or LPS (5 mg/kg body weight, oropharyngeal). Within 2 hrs of challenge, a subset of each was given either Ang-(1-7), PNA5, or peptide-free vehicle via different routes of administration: oropharyngeal or subcutaneous. Markers of inflammation in the lung were assessed within 72 hrs for each set of animals. RESULTS: During Mycoplasma infection, one high dose of Ang-(1-7) delivered to the lungs reduced neutrophilia and Muc5AC, as well as TNF-α and keratinocyte chemoattractant (KC). In line with severe COVID-related ARDS, a single dose of the Ang-(1-7) analog, PNA5, delivered subcutaneously to LPS-challenged mice led to significant protection against key features of ARDS: vascular permeability and pulmonary edema, neutrophil influx into the lung and TNF-α production. CONCLUSIONS: Ang1-7 has been shown by others to play a protective role to a variety of stimuli in a myriad of organs. Our new findings demonstrate that Ang1-7 and PNA5 can protect against both live Mp and LPS-induced lung inflammation. Replacement of Ang-(1-7) in ALI/ARDS patients, including severe COVD-19 patients, with an Ang-(1-7) replacement peptide such as PNA5, could be ideal adjunctive therapy to treat ALI/ARDS and support lung health and organ protection.