C1q binds to the Fc region of IgG hexamers on a pulmonary endothelial surface, resulting in the activation and assembly of two copies each of the serine proteases C1r and C1s, thus forming a C1 complex. The C1 complex cleaves C4 to C4b on a surface, which is processed to C4d and remains covalently bound. C4b, along with C2b, forms a C3 convertase. C3 convertase cleaves C3, releasing C3a into the fluid phase, while C3b and C3d remain bound to the cell surface, amplifying the cascade and forming the C5 convertase, which eventually facilitates the formation of the MAC (aka C5b-9). MAC disrupts endothelial integrity, resulting in vascular leak. At the same time, chemokines and anaphylatoxins, such as C3a and C5a, result in neutrophil activation. Subsequent neutrophil degranulation and the formation of NETs perpetuate injury. This ongoing injury results in moderate-to-severe lung damage, which, in its worst form, is characterized by histologic evidence of injury (such as septal thickening and hyaline membranes in humans), pulmonary inflammation, alveolar-capillary barrier disruption, and physiologic dysfunction, such as impaired gas exchange.