A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Ageing mechanisms that contribute to tissue remodeling in lung disease.

Age is a major risk factor for chronic respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and certain phenotypes of asthma. The recent COVID-19 pandemic also highlights the increased susceptibility of the elderly to acute respiratory distress syndrome (ARDS), a diffuse inflammatory lung injury with often long-term effects (ie parenchymal fibrosis). Collectively, these lung conditions are characterized by a pathogenic reparative process that, rather than restoring organ function, contributes to structural and functional tissue decline. In the ageing lung, the homeostatic control of wound healing following challenge or injury has an increased likelihood of being perturbed, increasing susceptibility to disease. This loss of fidelity is a consequence of a diverse range of underlying ageing mechanisms including senescence, mitochondrial dysfunction, proteostatic stress and diminished autophagy that occur within the lung, as well as in other tissues, organs and systems of the body. These ageing pathways are highly interconnected, involving localized and systemic increases in inflammatory mediators and damage associated molecular patterns (DAMPs); along with corresponding changes in immune cell function, metabolism and composition of the pulmonary and gut microbiomes. Here we comprehensively review the roles of ageing mechanisms in the tissue remodeling of lung disease.