Direct injury to alveolar epithelium is found in some causes of ARDS depending on the types of the insults. Mechanical stress, such as mechanical ventilation, can cause direct injury to epithelium.

Mechanical stress induces necrosis of epithelial cells and activation of some specific inflammatory signaling pathways in epithelial cells which in turn causes the secondary inflammatory injury (Slutsky and Ranieri, 2013). Mechanical ventilation can cause lung overdistention and disrupt epithelial tight junctions and adherent junctions (Wang et al., 2011). The correlation of ventilation and induced epithelial injury has been examined in animal models showing high tidal volume ventilation provokes epithelial injury while low tidal volume ventilation is able to reduce the damage in epithelium (Slutsky and Ranieri, 2013). Likewise, decreased epithelium injury is observed in ARDS patients treated with low tidal volume ventilation.             Viral infection can cause pneumonia which is the most common etiology of ARDS. Particularly, influenza virus infection results in both direct and inflammatory injury to epithelium. The type of epithelial cells which influenza viruses target is related to the specificity of the hemagglutinin (HA) expressed on the surface of the virus and the specific sialic acid residing on the epithelial cell surface (Herold et al.

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, 2015). Avian influenza viruses preferentially infect AEC-II cells and cause pneumonia. Once HA binds to sialic acid, virus enter AEC-II cells by endocytosis, replicate, and release viral particles causing AEC-II cell death (Hashimoto et al., 2007).            Bacterial infection can cause direct injury to epithelial cells by their exotoxins, in addition to inducing inflammatory injury. For instance, pseudomonas produces exoenzymes resulting in lysis of epithelial cells.

These exoenzymes disrupt integrin survival signalling and activate intrinsic apoptosis pathways (Wood et al., 2015) causing epithelial cell death. Gram-positive infection also induces alveolar epithelial cells lysis by their toxins (e.g. pneumolysin) forming transmembrane pores in host epithelial cells (Rubins and Janoff, 1998). Besides exoenzymes, hydrogen peroxide released from bacterial causes DNA damage in alveolar epithelial cells and results in apoptosis  (Rai et al., 2015).