Severe COVID-19 infection causes coagulopathies leading to stroke, pulmonary embolism, DVT,and disseminated intravascular coagulation (DIC). These complications of COVID-19 infectionare often lethal and can lead to permanent disability in survivors. COVID-19-inducedcoagulopathy is atypical of most respiratory viral infections and it is important to understand thebasis for these effects. Secretoglobin 1A1 (SCGB1A1, also known as CC10, CC16, CCSP, anduteroglobin) is a small globular immunomodulatory protein that is highly expressed in normallungs by Club cells. Club cells are injured during COVID-19 infection, by the extremeinflammatory response and/or by direct viral infection. Club cell depletion results in SCGB1A1deficiency. SCGB1A1 is important not only in maintaining lung homeostasis, function, and repair,but also circulates in the blood where it likely has additional homeostatic functions. SCGB1A1 isknown to inhibit platelet aggregation and Factor XIIIa transglutaminase activity in vitro and maytherefore play a role in vascular and/or blood homeostasis particularly as relates to balancingcoagulation responses. SCGB1A1 is also known to be chemically modified by exposure toreactive oxygen and nitrogen species (ROS/RNS) during severe inflammatory responses in thelungs and the impact of these modifications on the anti-thrombotic activities of SCGB1A1 meritsinvestigation. The proposed research will investigate the effects of ROS/RNS modification ofSCGB1A1 on coagulation and clot formation in vitro, as well as in an animal model, and then willevaluate the potential depletion of SCGB1A1 and ROS/RNS-mediated modifications of nativeSCGB1A1 in COVID-19 patients and the potentiation of thrombosis in COVID-19 patients.
Public Health Relevance Statement: The proposed research would contribute fundamental knowledge to our understanding of how severe
inflammation can impact local and systemic coagulation and regulation of vascular permeability through
a completely new and unanticipated mechanism. It could lead not only to improved management of
conditions like severe COVID-19 infection but also to new therapeutic approaches that could enhance
health, lengthen life, and reduce illness and disability.
Project Terms: Adhesions ; Aerosols ; Asthma ; Bronchial Asthma ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood ; Blood Reticuloendothelial System ; Blood Coagulation Disorders ; Coagulation Disorder ; Coagulopathy ; bleeding disorder ; clotting disorder ; Blood Platelets ; Marrow platelet ; Platelets ; Thrombocytes ; Blood Vessels ; vascular ; Blood capillaries ; capillary ; Cells ; Cell Body ; Centers for Disease Control and Prevention (U.S.) ; CDC ; Centers for Disease Control ; Centers for Disease Control and Prevention ; United States Centers for Disease Control ; United States Centers for Disease Control and Prevention ; Complication ; Cessation of life ; Death ; Disseminated Intravascular Coagulation ; Consumption Coagulopathy ; Dyspnea ; Breathlessness ; Endothelium ; Equilibrium ; balance ; balance function ; Factor XIIIa ; Activated Blood Coagulation Factor XIII ; Activated Factor XIII ; Fibrinoligase ; Family ; Future ; Health ; Heart Diseases ; Cardiac Diseases ; Cardiac Disorders ; heart disorder ; Homeostasis ; Autoregulation ; Physiological Homeostasis ; Hospitalization ; Hospital Admission ; Human ; Modern Man ; Hypertension ; Vascular Hypertensive Disease ; Vascular Hypertensive Disorder ; high blood pressure ; hyperpiesia ; hyperpiesis ; hypertensive disease ; In Vitro ; indexing ; Inflammation ; Interleukin-1 ; IL-1 ; IL1 ; Interleukin I ; Lymphocyte-Stimulating Hormone ; Macrophage Cell Factor ; T Helper Factor ; lymphocyte activating factor ; Interleukin-6 ; B cell differentiation factor ; B cell stimulating factor 2 ; B-Cell Differentiation Factor ; B-Cell Differentiation Factor-2 ; B-Cell Stimulatory Factor-2 ; BCDF ; BSF-2 ; BSF2 ; HPGF ; Hepatocyte-Stimulating Factor ; Hybridoma Growth Factor ; IFN-beta 2 ; IFNB2 ; IL-6 ; IL6 Protein ; MGI-2 ; Myeloid Differentiation-Inducing Protein ; Plasmacytoma Growth Factor ; interferon beta 2 ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lung ; Lung Respiratory System ; pulmonary ; Chronic Obstructive Airway Disease ; COPD ; Chronic Obstruction Pulmonary Disease ; Chronic Obstructive Lung Disease ; Chronic Obstructive Pulmonary Disease ; Nitrogen ; Oxygen ; O element ; O2 element ; Patients ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Platelet aggregation ; Play ; Transglutaminases ; Proteins ; Pulmonary Embolism ; Pulmonary Fibrosis ; lung fibrosis ; Pulmonary Surfactants ; Lung Surfactant ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Adult Respiratory Distress Syndrome ; ARDS ; Acute Respiratory Distress ; Acute Respiratory Distress Syndrome ; Adult ARDS ; Adult RDS ; Da Nang Lung ; Shock Lung ; Stiff lung ; wet lung ; Respiratory Insufficiency ; lung insufficiency ; Role ; social role ; Stroke ; Apoplexy ; Brain Vascular Accident ; Cerebral Stroke ; Cerebrovascular Apoplexy ; Cerebrovascular Stroke ; brain attack ; cerebral vascular accident ; cerebrovascular accident ; Thrombosis ; thrombotic disease ; thrombotic disorder ; Uteroglobin ; Blastokinin ; Vaccines ; Veterans ; Virus Diseases ; Viral Diseases ; viral infection ; virus infection ; virus-induced disease ; Virus ; ferric chloride ; iron perchloride ; iron sesquichloride ; cytokine ; Measures ; Mediating ; Vascular Permeabilities ; Reactive Oxygen Species ; Active Oxygen ; Oxygen Radicals ; Pro-Oxidants ; improved ; Acute ; repaired ; repair ; Phase ; Biological ; Survivors ; Coronavirus ; Coronaviridae ; corona virus ; Chemicals ; alveolar epithelium ; Lung Alveolar Epithelia ; disability ; Individual ; Hypoxia ; Hypoxic ; Oxygen Deficiency ; Chemosensitization ; Chemosensitization/Potentiation ; Potentiation ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; Exposure to ; Inflammatory ; Knowledge ; Life ; Investigation ; Reaction ; American ; Isoforms ; Protein Isoforms ; respiratory virus ; Cellular injury ; cell damage ; cellular damage ; damage to cells ; injury to cells ; cell injury ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Immunomodulation ; immune modulation ; immune regulation ; immunologic reactivity control ; immunomodulatory ; immunoregulatory ; immunoregulation ; Reporting ; (TNF)-α ; Cachectin ; Macrophage-Derived TNF ; Monocyte-Derived TNF ; TNF ; TNF A ; TNF Alpha ; TNF-α ; TNFA ; TNFα ; Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; TNF gene ; Regulation ; Modeling ; response ; viral respiratory infection ; Viral Respiratory Tract Infection ; Reactive Nitrogen Species ; Inflammatory Response ; Vascular Endothelial Cell ; preventing ; prevent ; Clotting ; Coagulation ; Coagulation Process ; in vivo ; in vivo Model ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Modification ; Development ; developmental ; aged ; innovation ; innovate ; innovative ; airway epithelium ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; inflammatory marker ; inflammation marker ; in vitro activity ; service member ; military member ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; military service ; COVID-19 patient ; COVID infected patient ; COVID patient ; COVID positive patient ; COVID-19 infected patient ; COVID-19 positive patient ; COVID19 patient ; COVID19 positive patient ; SARS-CoV-2 infected patient ; SARS-CoV-2 patient ; SARS-CoV-2 positive patient ; coronavirus disease 2019 infected patient ; coronavirus disease 2019 patient ; coronavirus disease 2019 positive patient ; coronavirus disease infected patient ; coronavirus disease patient ; coronavirus disease positive patient ; coronavirus patient ; patient infected with COVID ; patient infected with COVID-19 ; patient infected with SARS-CoV-2 ; patient infected with coronavirus disease ; patient infected with coronavirus disease 2019 ; patient infected with severe acute respiratory syndrome coronavirus 2 ; patient with COVID ; patient with COVID-19 ; patient with COVID19 ; patient with SARS-CoV-2 ; patient with coronavirus disease ; patient with coronavirus disease 2019 ; patient with severe acute respiratory distress syndrome coronavirus 2 ; severe acute respiratory syndrome coronavirus 2 infected patient ; severe acute respiratory syndrome coronavirus 2 patient ; severe acute respiratory syndrome coronavirus 2 positive patient ; severe COVID-19 ; life-threatening COVID ; life-threatening COVID-19 ; life-threatening SARS-CoV-2 ; life-threatening coronavirus disease ; life-threatening coronavirus disease 2019 ; life-threatening severe acute respiratory syndrome coronavirus 2 ; serious COVID ; serious COVID-19 ; serious SARS-CoV-2 ; serious coronavirus disease ; serious coronavirus disease 2019 ; serious severe acute respiratory syndrome coronavirus 2 ; severe COVID ; severe COVID19 ; severe SARS-CoV-2 ; severe coronavirus disease ; severe coronavirus disease 19 ; severe coronavirus disease 2019 ; severe severe acute respiratory syndrome coronavirus 2 ; SARS-CoV-2 infection ; COVID-19 infection ; COVID19 infection ; SARS-CoV2 infection ; Severe acute respiratory syndrome coronavirus 2 infection ; coronavirus disease 2019 infection ; infected with COVID-19 ; infected with COVID19 ; infected with SARS-CoV-2 ; infected with SARS-CoV2 ; infected with coronavirus disease 2019 ; infected with severe acute respiratory syndrome coronavirus 2 ; Immune mediated destruction ; Immune destruction ;
