Most SARS-CoV2 infections will not develop into severe COVID-19. However, in some patients, lung infection leads to the activation of alveolar macrophages and lung epithelial cells that will release proinflammatory cytokines. IL-6, TNF, and IL-1β increase expression of cell adhesion molecules (CAMs) and VEGF, thereby increasing permeability of the lung endothelium and reducing barrier protection, allowing viral dissemination and infiltration of neutrophils and inflammatory monocytes. In the blood, these cytokines will stimulate the bone marrow to produce and release immature granulocytes, that return to the lung and further increase inflammation, leading to acute respiratory distress syndrome (ARDS). This lung-systemic loop leads to cytokine storm syndrome (CSS). Concurrently, the acute phase response increases the production of platelets, fibrinogen and other pro-thrombotic factors. Systemic decrease in ACE2 function impacts the Renin-Angiotensin-Kallikrein-Kinin systems (RAS-KKS) increasing clotting. The combination of acute lung injury with RAS-KKS unbalance is herein called COVID-19 Associated Lung Injury (CALI). This conservative two-hit model of systemic inflammation due to the lung injury allows new intervention windows and is more consistent with the current knowledge.

大多数 SARS-CoV2 感染不会发展为严重的 COVID-19。然而，在一些患者中，肺部感染导致肺泡巨噬细胞和肺上皮细胞激活，释放促炎细胞因子。IL-6、TNF和IL-1β增加细胞粘附分子（CAM）和VEGF的表达，从而增加肺内皮的通透性并降低屏障保护，从而允许病毒传播和中性粒细胞和炎性单核细胞的浸润。在血液中，这些细胞因子会刺激骨髓产生和释放未成熟的粒细胞，这些粒细胞返回肺部并进一步加剧炎症，导致急性呼吸窘迫综合征（ARDS）。这种肺-全身循环会导致细胞因子风暴综合征（CSS）。同时，急性期反应增加血小板、纤维蛋白原和其他促血栓形成因子的产生。ACE2 功能的全身性下降会影响肾素-血管紧张素-激肽释放酶-激肽系统 (RAS-KKS)，从而增加凝血。急性肺损伤与 RAS-KKS 不平衡的组合在本文中称为 COVID-19 相关肺损伤 (CALI)。这种由肺损伤引起的全身炎症的保守两次打击模型允许新的干预窗口并且更符合当前的知识。