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Review
. 2020 Jun 26:11:1626.
doi: 10.3389/fimmu.2020.01626. eCollection 2020.

Overview: Systemic Inflammatory Response Derived From Lung Injury Caused by SARS-CoV-2 Infection Explains Severe Outcomes in COVID-19

Rafael B Polidoro  1 , Robert S Hagan  2 , Roberta de Santis Santiago  3 , Nathan W Schmidt  1
Affiliations
Review

Overview: Systemic Inflammatory Response Derived From Lung Injury Caused by SARS-CoV-2 Infection Explains Severe Outcomes in COVID-19

Rafael B Polidoro et al. Front Immunol. .

Abstract

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.

Keywords: ARDS; COVID-19; SARS-CoV2; bisphosphonates; inflammatory monocytes; kallikrein-kinin system; renin-angiotensin system; severe COVID-19.

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Figures

Figure 1
Figure 1
The four phases of SARS-CoV2 infection. (1) Upper and lower respiratory tract infection (outpatients); (2) COVID-19 associated lung injury (CALI), in which some patients will be hospitalized (inpatients); (3) Systemic inflammatory response syndrome (SIRS), in which bone marrow and liver acute phase response accumulate pro-thrombotic factors resulting in blood clots/thrombosis; (4) The sustained loop between lung and systemic inflammation results in multi-organ vascular dysfunction and cytokine storm syndrome.
Figure 2
Figure 2
Two-hit model of systemic inflammation derived from COVID-19 associated lung injury.
See this image and copyright information in PMC

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