Abstract Body: Background and Hypothesis: Chronic lung inflammation is a significant risk factor for heart failure. There are no effective treatments that target inflammation of the heart-lung continuum to stop heart failure. Anti-inflammatory peptide drugs are powerful treatment options, but their efficacy is compromised during systemic delivery. Pulmonary delivery targets lungs, facilitates drug absorption effectively due to the large surface area of the lungs, and instantly carry the drugs to the heart via pulmonary vein, thus allowing the heart and lung tissues to receive peptide drugs with minimal degradation. However, inhalers cannot deliver aqueous formulations of peptide drugs and mechanical stress of nebulizers cause their degradation/functional loss. We reported that Droplette Micromist Technology Device (DMTD) generates a micromist that packages nucleic acids and peptides without degradation. We also showed that systemic delivery of peptide drug NP-6A4 mitigates cardiac dysfunction in rat models of metabolic syndrome via activation of anti-inflammatory cytokine-miRNA networks and protective autophagy. Thus, we hypothesized that if pulmonary delivery of NP-6A4 micromist mitigates lung inflammation, this treatment could arrest the inflammation of the heart-lung continuum.
Methods and Results: Real-time changes in Cell Index (CI) of human primary alveolar epithelial cells (hPAEiCs) when exposed to Sars CoV2 Spike protein (SP) (50nM; n=3-5) with or without NP-6A4 (400nM) (n=6) were assessed. Lung inflammation was induced in Wistar rats (n=12) via aerosol inhalation of S. typhimurium lipopolysaccharide (LPS: 3mg/mL; 23 minutes on 2 alternate days) and treated with DMTD-pulmonary delivery of NP-6A4 (300μ L of 10mg/kg/day delivered in 30 seconds after LPS exposure). CI of hPAEiCs was abolished by SP, but NP-6A4 fully restored the CI (p<0.05). Chest X-rays of LPS-treated rats exhibited white/hazy regions indicating pneumonia, but NP-6A4 pulmonary delivery completely prevented this response to LPS.
Conclusion: These data suggest that cardioprotective NP-6A4 effectively suppresses lung cell inflammation caused by SP and LPS and DMTD-pulmonary delivery is a new and useful technique for delivery of cardio-pulmonary protective peptide drugs.