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PLoS Comput Biol ; 17(3): e1008810, 2021 03.
Article in English | MEDLINE | ID: covidwho-1121603


Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.

COVID-19/complications , COVID-19/genetics , Extracellular Traps/genetics , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/genetics , Models, Biological , SARS-CoV-2/genetics , Thrombosis/etiology , Thrombosis/genetics , Algorithms , Cell Degranulation/genetics , Computational Biology , Gene Expression Regulation , Gene Regulatory Networks , Genetic Predisposition to Disease , Humans , Pandemics , Protein Interaction Maps , Pulmonary Embolism/etiology , Pulmonary Embolism/genetics , Viral Proteins/genetics
PLoS One ; 15(12): e0242318, 2020.
Article in English | MEDLINE | ID: covidwho-955356


The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions. We studied the effects of colchicine pre-treatment on oleic acid-induced ARDS in rats. Rats were treated with colchicine (1 mg/kg) or placebo for three days prior to intravenous oleic acid-induced ALI (150 mg/kg). Four hours later they were studied and compared to a sham group. Colchicine reduced the area of histological lung injury by 61%, reduced lung edema, and markedly improved oxygenation by increasing PaO2/FiO2 from 66 ± 13 mmHg (mean ± SEM) to 246 ± 45 mmHg compared to 380 ± 18 mmHg in sham animals. Colchicine also reduced PaCO2 and respiratory acidosis. Lung neutrophil recruitment, assessed by myeloperoxidase immunostaining, was greatly increased after injury from 1.16 ± 0.19% to 8.86 ± 0.66% and significantly reduced by colchicine to 5.95 ± 1.13%. Increased lung NETosis was also reduced by therapy. Circulating leukocytosis after ALI was not reduced by colchicine therapy, but neutrophils reactivity and CD4 and CD8 cell surface expression on lymphocyte populations were restored. Colchicine reduces ALI and respiratory failure in experimental ARDS in relation with reduced lung neutrophil recruitment and reduced circulating leukocyte activation. This study supports the clinical development of colchicine for the prevention of ARDS in conditions causing ALI.

Acute Lung Injury/drug therapy , Colchicine/pharmacology , Lung/drug effects , Respiratory Distress Syndrome/drug therapy , Acute Lung Injury/blood , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Disease Models, Animal , Humans , Lung/pathology , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Oleic Acid/toxicity , Rats , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology