The role of C5a in acute lung injury induced by highly pathogenic viral infections

Abstract

The complement system, an important part of innate immunity, plays a critical role in pathogen clearance. Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. In highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic C5a were produced as a result of excessive complement activaiton. Overproduced C5a displays powerful biological activities in activation of phagocytic cells, generation of oxidants, and inflammatory sequelae named “cytokine storm”, and so on. Blockade of C5a signaling have been implicated in the treatment of ALI induced by highly pathogenic virus. Herein, we review the literature that links C5a and ALI, and review our understanding of the mechanisms by which C5a affects ALI during highly pathogenic viral infection. In particular, we discuss the potential of the blockade of C5a signaling to treat ALI induced by highly pathogenic viruses.

Clinical Features and Radiological Findings of Adenovirus Pneumonia Associated with Progression to Acute Respiratory Distress Syndrome: A Single Center Study in 19 Adult Patients

“…It is known that adenovirus causes cytolysis, which accounts for tissue damage, and damaged pulmonary capillaries can contribute to respiratory failure (24). Another possible explanation is the unregulated complement activation, producing C5a and resulting in activation of phagocytic cells, generation of oxidants, release of histones, and, eventually, a cytokine storm (2526). Many previous cases of respiratory failure resulting from influenza A viruses H1N1, H5N1, and H7N9, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus pneumonia were associated with cytokine storms (27).…”

Acute Respiratory Distress Syndrome as an Organ Phenotype of Vascular Microthrombotic Disease: Based on Hemostatic Theory and Endothelial Molecular Pathogenesis

“…[84][85][86] However, its relationship between ARDS and complement activation has not been explored even though the role of C5b-9 was suspected to contribute to its pathogenesis 86 and C5a in highly pathogenic viral infections was also implicated in acute lung injury. 87 The activation of complement system is one of the key events in defense mechanism against sepsis. Its protective function for host rapidly identifies and eliminates invading pathogen.…”

The Role of Complement in Transfusion-Related Acute Lung Injury

“…Furthermore, as discussed above, C5a plays an important role in ROS generation and formation of NETs. Similar to TRALI, ROS and NETs have also been shown to play a role in ALI [69,[77][78][79]. Notably, it was suggested that intravascular activation of PMNs by C5a may be related to the generation of ROS, resulting in the onset of ALI [78].…”

“…Activation of the complement system plays an important role in ALI caused by highly pathogenic viruses such as influenza virus A (H5N1 and H7N9) and severe acute respiratory syndrome [69]. It has been shown that infection of the human host with highly pathogenic viruses such as influenza A results in complement activation and formation of C5a [69,70]. In addition, BALF and serum of mice and humans infected with fatal H1N1 virus contained increased levels of C5a [71,72].…”

“…Furthermore, it has been shown that ALI induced by H5N1 played a relevant role by excessive complement activation including C5a generation [73]. Several murine in vivo studies using H1N1 and H5N1 as ALI inducers have shown beneficial effects of blocking C5a or C5aR in ALI [69,[72][73][74][75]. In addition, C5a can also directly impact vascular permeability by activating endothelial cells [22], which are also activated in TRALI [76].…”