# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 3 Pathogenesis of COVID-19-Induced Lung Injury
### COVID-19 Immunopathology  
Efficient clearance of SARS-CoV-2 with minimal damage to the host requires a coordinated innate immune response to control infection and stimulate organization of a targeted adaptive immune response. In severe disease, however, numerous mechanisms cause dysregulation of the innate response, leading to significant immune-mediated damage affecting the lungs as well as other organ systems. Furthermore, the disturbed innate response leads to a late, ineffective adaptive immune response, setting the stage for critical illness [59]. Several studies point toward inflammasome activation as a key mechanism in COVID-19 immunopathogenesis [60; 69; 70]. This is supported by high association with disease severity in key mediators associated with inflammasome activation in serum and/or BALF. These include lactate dehydrogenase--an alarmin released during pyproptosis, IL18 and IL-18--cytokines cleaved by activated caspases, as well as a variety of cytokines strongly induced by IL-18, including IL-6, IL8, and TNF-\(\kappa\)[71; 72]. By interrogating a combination of biomarkers, [PERSON] and colleagues identified increased alveolar epithelial necrosis in COVID-19 patients with vs. without ARDS. Using a 24 h experimental model of COVID-19 lung injury, the authors demonstrated significant involvement of pyproptosis and necroptosis--both of which are necrotic pathways activated by inflammasome formation [73]. The exact mechanisms of inflammasome activation in these contexts may be multifactorial, as evidence exists for both PRR-mediated DAMP detection and viral accessory protein mechanisms. These findings suggest that COVID-19 may induce extensive inflammasome activation early in the disease phase in both alveolar epithelial and endothelial cells. Moreover, viral suppression of IFN-I/III release likely exacerbates this phenomenon as unfettered viral replication would enhance inflammasome activation and alveolar epithelial necrosis [60]. Lung-resident macrophages are also subject to inflammasome activation. A recent study demonstrated a novel mechanism in lung macrophages induced by direct SARS-CoV-2 infection. Using isolated human lung macrophages and a humanized mouse model of COVID-19, [PERSON] and colleagues found that ACE2 and CD16-mediated infection led to inflammasome activation, release of IL-1\(\beta\) and IL-18, and pyroptosis, driving significant lung inflammation [70]. Interestingly, inhibition of NLRP3 decreased lung pathology but led to the release of infectious virus, suggesting pyroptosis in infected macrophages is simultaneously virus-killing and immunopathologic [70]. These findings are consistent with depleted AMs in BALF of patients with critical COVID-19. Furthermore, the depleted AMs were replaced with large infiltrates of monocyte-derived macrophages which expressed inflammatory phenotypes characterized by expression of IL-18, IL-6, IL-8, CXCL10, and TNF-\(\alpha\). Gene expression profiling of these macrophages was suggestive of hyperactivation due to similarity with the profiles of macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) [74]. Thus, while AMs are vital in pulmonary immune homeostasis under normal conditions, SARS-CoV-2 infection appears to trigger inflammasome activation and pyroptosis of AMs, leading to lung pathology. Circulating monocytes also play an important role in COVID-19 immunopathology. PBMCs isolated from patients with severe COVID-19 bear striking differences to those isolated from mild cases. Specifically, expression of surface markers in these PBMC populations skews towards CD14 high, S100 Ahigh, IL-6 high, and HLA-DRlow, indicating high pro-inflammatory activity and low antigen-presenting capacity [74]. Furthermore, the hypoxemic milieu of severe COVID-19 can reduce PBMC antiviral activity via the transcriptional corepressor hypoxia-inducible factor-1\(\alpha\) (HIF-1\(\alpha\)).