# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 2 Pathophysiology of Acute Lung Injury
### Cellular and Molecular Mechanisms of Lung Injury
Through binding IL-1R, IL-1\(\beta\) activates transcription of IL-6, IL-8, tumor necrosis factor (TNF), type 1 interferon (IFN-I), and other cytokines and chemokines. Caspase-1 also cleaves gasdermin D (GDSMD), leading to formation of plasma membrane pores and eventual pyroptosis. Figure 1: Alveolar changes during ALI. Under normal conditions (left), gas exchange is facilitated by a thin epithelial–endothelial barrier which is maintained by the collective functions of alveolar epithelial cells (pneumocytes), endothelial cells, and alveolar macrophages. During ALI (right), damage to the epithelial–endothelial barrier sets in motion a cascade of inflammatory processes that exacerbate tissue damage, accelerate edema formation, and critically impair gas exchange. Figure created with BioRender.com. Pyrotosis inherently causes release of DAMPs and other pro-inflammatory mediators, which further propagates the immune response [16]. These mechanisms signal through paracrine and autocrine mechanisms to augment the host immune response. Elevated concentrations of pro-inflammatory mediators in the pulmonary milieu facilitates the recruitment of circulating leukocytes to participate in host defense. This process is initiated in pulmonary microvascular endothelial cells, wherein inflammatory cytokines induce destabilization of intercellular junctions, shedding of the endothelial glycocalyx, secretion of chemokines, and expression of leukocyte adhesion molecules such as intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and dipeptidase 1 [18; 19]. These changes facilitate the adhesion and diapedesis of circulating leukocytes such as neutrophils and monocytes, which migrate into the tissue along established C-X-C motif and/or C-C motif chemokine gradients [20]. The recruited leukocytes then employ a suite of antimicrobial tactics including phagocytosis, formation of extracellular traps (e.g., neutrophil extracellular traps, NETs), and secretion of proteases and reactive oxygen species (ROS) to attempt to neutralize the threat. While these functions may be beneficial or essential for host defense, they also consequently inflict significant damage to host tissues [21]. As tissue damage increases, pre-existing alveolar-capillary barrier dysfunction is exacerbated in an accelerating manner. Breakdown of the alveolar-capillary barrier increases vascular permeability, leading to leakage of fluid and proteins into the alveolar space (i.e., edema). Alveolar edema is further exacerbated by damage to epithelial and endothelial cells which impair homeostatic alveolar and interstitial fluid clearance mechanisms [13; 22]. Moreover, edema impairs the surfactant function, leading to increased surface tension and risk of atelectasis (alveolar collapse) [23]. In addition to impaired alveolar ventilation, ALI is often associated with impairment in pulmonary capillary perfusion due to coagulation and subsequent formation of physiologic dead space. In this process, activated endothelial cells initiate the extrinsic coagulation cascade via upregulation of tissue factor, leading to activation of thrombin and formation of fibrin clots [4]. Exposure of subendothelial collagen also leads to integrin- and glycoprotein receptor-mediated platelet binding [24]. Importantly, many coagulative mechanisms interact with the other pathomechanisms of ALI. For example, binding of thrombin to protease-activated receptor-1 (PAR\({}_{1}\)) drives actomyosin shifts and increases in paracellular permeability. Moreover, neutrophils play a synergistic role in fibrin clot formation and stability through NETosis [19]. Thus, coagulation, while protective under normal conditions, can become an important contributor to the pathology of ALI [24].