# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 2 Pathophysiology of Acute Lung Injury
### Cellular and Molecular Mechanisms of Lung Injury  
The alveoli, otherwise known as the lung's functional respiratory unit, is critically involved in ALI (Figure 1). The alveoli are thin-walled air sacs approximately 200 um in diameter composed of ultra-thin alveolar type 1 epithelial cells and surfactant-producing alveolar type 2 epithelial cells [12]. To facilitate gas exchange, the alveoli are surrounded by dense networks of pulmonary capillaries lined with pulmonary microvascular endothelial cells. Under normal physiological circumstances, epithelial and endothelial cells form tight barriers that actively restrict and modulate fluid flux to mitigate formation of edema [13]. This function is complemented by resident immune cells, including alveolar macrophages which employ phagocytic and anti-microbial functions to maintain a clear epithelial surface for gas exchange. During ALI, however, epithelial and/or endothelial insults activate host inflammatory responses leading to a breakdown of the barrier function, formation of alveolar edema, and impairment of gas exchange [11]. \begin{table}
\begin{tabular}{c c c c} \hline  & **Mild** & **Moderate** & **Severe** \\ \hline Timing & Within 1 week of a known clinical indult, or new/worsening respiratory symptoms & 200 mmHg \textless{} PaO\textgreater{}/FiO\textgreater{} \(\leq\) & 100 mmHg \textless{} PaO\textgreater{}/FiO\textgreater{} \(\leq\) & 100 mmHg \textless{} PaO\textgreater{}/FiO\textgreater{} \\ Degree of Hypoxemia & 300 mmHg & 200 mmHg & 100 mmHg \textless{} PaO\textgreater{}/FiO\textgreater{} \\ PEEP Requirement & PEEP or CPAP \textgreater{} 5 cm H\textgreater{}O & PEEP \textgreater{} 5 cm H\textgreater{}O & PEEP \textgreater{} 5 cm H\textgreater{}2O \\ Edema & Respiratory failure not fully explained by cardiac failure or fluid overload. Require objective assessment & to exclude hydrostatic edema if no risk factors present \\ Chest Imaging & Bilateral opacities, not fully explained by pleural effusions, lobar/lung collapse, or nodules \\ \hline \end{tabular}
\end{table} 
Table 1: The Berlin definition of acute respiratory distress syndrome. Primary damage to the alveolar-capillary barrier can occur from a wide variety of factors. For example, during pneumonia, the epithelium is initially damaged directly by pathogens through, e.g., bacterial pore-forming toxins or lytic viral replication [14; 15]. Direct damage can also occur from hypercapnia or hyperoxia, which can impair the alveolar epithelium by inducing mitochondrial dysfunction and free radical formation. Moreover, mechanical stretch induced by positive-pressure ventilation can disrupt epithelial tight junctions and cause cellular detachment from the basement membrane. In parallel, the endothelium may be damaged initially by similar factors including pathogens, ventilator-induced mechanical stretch, and circulating inflammatory mediators [4]. Collectively, these and other insults directly impair the alveolar-capillary barrier function and initiate a cascade of inflammatory events, which favors the development of ALI. Primary damage to the alveolar-capillary barrier, if significant, is followed by a wave of immune activation [11]. This is initiated by pattern recognition receptors (PRRs), which are activated by pathogen-associated molecular patterns (PAMPs, e.g., bacterial lipopolysaccharide-charide) and damage-associated molecular patterns (DAMPs, e.g., extracellular DNA). Various PRRs are involved in ALI, including toll-like receptors (TLRs), retinoic acid-inducible gene-I-like receptors (RLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), and C-type lectin receptors (CLRs), among others. Upon activation, PRRs initiate signaling cascades which drive release of pro-inflammatory mediators, production of anti-microbial agents, and induction of cell death pathways [1; 16]. For example, numerous inputs stimulate NLRP3 inflammasome formation, which activates caspase-1, leading to cleavage of the cytokines interleukin (IL)-1\(\beta\) and IL-18 into their active forms [17].