Decoding fibrosis in nonresolvable COVID-19: a role for myeloid-specific HIF1A deletion

A complication of viral lung infections is the development of pulmonary fibrosis. This phenomenon is most evident in patients with COVID-19, where in its most aggressive form patients developed nonresolvable (NR) COVID-19 requiring lung transplantation. NR-COVID-19 was characterized by the presentation of a fulminant fibrotic lung injury that progressed rapidly, even in patients with limited comorbidities. However, the mechanisms that led to this rapidly progressing form of fibrosis are not fully understood. A common clinical manifestation in the most severe cases of COVID-19 was the presence of "silent" hypoxemia. Thus, we hypothesized that a dysfunctional hypoxic response may result in exacerbated lung injury seen in patients with severe forms of COVID-19. Our results demonstrate that despite increased expression of hypoxia-inducible factor 1A (HIF1A) and its downstream mediator adenosine A_2B receptor (ADORA2B), reduced macrophage HIF1A was observed in patients with severe COVID-19, including NR-COVID-19. Utilizing mice lacking HIF1A in myeloid cells using the lysozyme M Cre promoter, we demonstrate that these mice present with increased lung inflammation and pulmonary fibrosis following chronic low-dose bleomycin treatment. The augmented lung injury was associated with reduced markers for alternatively activated macrophages also observed in NR-COVID-19 lungs. These results point to reduced myeloid HIF1A as a mechanism that can lead to exacerbated lung injury in mice, which parallels the rapid fibrotic response observed in NR-COVID-19. Collectively, our results point to using HIF1A stabilizers as a potential avenue to prevent the development of rapidly progressing postviral lung fibrosis. However, special care is necessary since chronic HIF1A activation is also linked to fibrotic outcomes.<b>NEW & NOTEWORTHY</b> Postviral-induced lung fibrosis represents a severe and potentially fatal outcome. This was most evident during the COVID-19 pandemic, where a subset of individuals presented with fulminant lung fibrosis requiring lung transplantation. The mechanisms that promote this exacerbated lung injury are not fully known. Herein, we demonstrate that mice lacking myeloid hypoxia-inducible factor 1A (HIF1A) develop an exacerbated lung injury response to bleomycin that was consistent with reduced macrophage HIF1A expression in nonresolvable (NR)-COVID-19, characterized by extensive lung fibrosis.