angiotensin-i and Orthomyxoviridae-Infections

Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19.

Topics: Acetates; Angiotensin I; Animals; Annexin A1; Anti-Inflammatory Agents; COVID-19; COVID-19 Drug Treatment; Disease Models, Animal; Docosahexaenoic Acids; Humans; Hydrogen Peroxide; Inflammation; Inflammation Mediators; Mice; Orthomyxoviridae Infections; Oxidants; Peptide Fragments; Peptides; Phosphodiesterase 4 Inhibitors; Pneumonia, Viral; Rolipram; Vasodilator Agents

Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium's protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.

Topics: Acute Lung Injury; Angiotensin I; Animals; Body Fluids; Coculture Techniques; Cystic Fibrosis Transmembrane Conductance Regulator; Cytokines; Female; Fibroblast Growth Factor 7; Humans; Inflammation Mediators; Influenza A Virus, H5N1 Subtype; Influenza, Human; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Permeability; Pulmonary Alveoli; Sodium-Potassium-Exchanging ATPase