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Hypothesis: Alpha-1-antitrypsin is a promising treatment option for COVID-19.
Bai, Xiyuan; Hippensteel, Joseph; Leavitt, Alida; Maloney, James P; Beckham, David; Garcia, Cindy; Li, Qing; Freed, Brian M; Ordway, Diane; Sandhaus, Robert A; Chan, Edward D.
  • Bai X; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, USA.
  • Hippensteel J; Division of Pulmonary Sciences and Critical Care Medicine, USA; Denver Health, Denver, CO, USA.
  • Leavitt A; Department of Obstetrics and Gynecology, USA.
  • Maloney JP; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, USA.
  • Beckham D; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Garcia C; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA.
  • Li Q; Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA; School of Public Health, San Diego State University, San Diego, CA, USA.
  • Freed BM; Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Ordway D; Department of Microbiology, Immunlogy, and Pathology, Colorado State University, Fort Collins, CO, USA.
  • Sandhaus RA; Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA.
  • Chan ED; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA; Departments of Academic Affairs and Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary Sciences and Critical Care Medicine, USA. Electronic address: ChanE@NJHealth.org.
Med Hypotheses ; 146: 110394, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-919589
Semantic information from SemMedBD (by NLM)
1. Definitive Treatment NEG_TREATS COVID-19
Subject
Definitive Treatment
Predicate
NEG_TREATS
Object
COVID-19
2. Agent TREATS COVID-19
Subject
Agent
Predicate
TREATS
Object
COVID-19
3. Serine Proteinase Inhibitors INHIBITS TMPRSS2
Subject
Serine Proteinase Inhibitors
Predicate
INHIBITS
Object
TMPRSS2
4. M Protei PART_OF C5203676
Subject
M Protei
Predicate
PART_OF
Object
C5203676
5. M Protei INTERACTS_WITH C1422064|59272
Subject
M Protei
Predicate
INTERACTS_WITH
Object
C1422064|59272
6. SERPINA1 wt Allele|SERPINA1 CAUSES Autophagy
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
CAUSES
Object
Autophagy
7. Coronavirus Infections CAUSES Middle East Respiratory Syndrome
Subject
Coronavirus Infections
Predicate
CAUSES
Object
Middle East Respiratory Syndrome
8. Anti-Inflammatory Agents STIMULATES NF-kappa B
Subject
Anti-Inflammatory Agents
Predicate
STIMULATES
Object
NF-kappa B
9. SERPINA1 wt Allele|SERPINA1 INHIBITS Leukocyte Elastase
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
INHIBITS
Object
Leukocyte Elastase
10. Serine Endopeptidases AFFECTS Acute Lung Injury
Subject
Serine Endopeptidases
Predicate
AFFECTS
Object
Acute Lung Injury
11. SERPINA1 wt Allele|SERPINA1 INHIBITS ADAM17 Protein|ADAM17
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
INHIBITS
Object
ADAM17 Protein|ADAM17
12. ACE2 gene|ACE2 INHIBITS Bradykinin
Subject
ACE2 gene|ACE2
Predicate
INHIBITS
Object
Bradykinin
13. Bradykinin CAUSES Increased capillary permeability (finding)
Subject
Bradykinin
Predicate
CAUSES
Object
Increased capillary permeability (finding)
14. Ability ASSOCIATED_WITH COVID-19
Subject
Ability
Predicate
ASSOCIATED_WITH
Object
COVID-19
15. SERPINA1 wt Allele|SERPINA1 INHIBITS thrombin
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
INHIBITS
Object
thrombin
16. Venous Thromboembolism COEXISTS_WITH COVID-19
Subject
Venous Thromboembolism
Predicate
COEXISTS_WITH
Object
COVID-19
17. Microthrombus COEXISTS_WITH COVID-19
Subject
Microthrombus
Predicate
COEXISTS_WITH
Object
COVID-19
18. DNA INHIBITS Elastases
Subject
DNA
Predicate
INHIBITS
Object
Elastases
19. Histones INHIBITS Elastases
Subject
Histones
Predicate
INHIBITS
Object
Elastases
20. Peptide Hydrolases INHIBITS Elastases
Subject
Peptide Hydrolases
Predicate
INHIBITS
Object
Elastases
21. Syndrome DISRUPTS endothelial cell apoptotic process
Subject
Syndrome
Predicate
DISRUPTS
Object
endothelial cell apoptotic process
22. Acute Lung Injury DISRUPTS endothelial cell apoptotic process
Subject
Acute Lung Injury
Predicate
DISRUPTS
Object
endothelial cell apoptotic process
23. Antiphospholipid Antibodies AUGMENTS Pre-Eclampsia
Subject
Antiphospholipid Antibodies
Predicate
AUGMENTS
Object
Pre-Eclampsia
24. Antiphospholipid Antibodies AUGMENTS COVID-19
Subject
Antiphospholipid Antibodies
Predicate
AUGMENTS
Object
COVID-19
25. Present COEXISTS_WITH Disease
Subject
Present
Predicate
COEXISTS_WITH
Object
Disease
26. alpha 1-Antitrypsin Deficiency PROCESS_OF Patients
Subject
alpha 1-Antitrypsin Deficiency
Predicate
PROCESS_OF
Object
Patients
27. Definitive Treatment NEG_TREATS COVID-19
Subject
Definitive Treatment
Predicate
NEG_TREATS
Object
COVID-19
28. Agent TREATS COVID-19
Subject
Agent
Predicate
TREATS
Object
COVID-19
29. Serine Proteinase Inhibitors INHIBITS TMPRSS2
Subject
Serine Proteinase Inhibitors
Predicate
INHIBITS
Object
TMPRSS2
30. M Protein, multiple myeloma PART_OF 2019 novel coronavirus
Subject
M Protein, multiple myeloma
Predicate
PART_OF
Object
2019 novel coronavirus
31. M Protein, multiple myeloma INTERACTS_WITH ACE2 gene|ACE2
Subject
M Protein, multiple myeloma
Predicate
INTERACTS_WITH
Object
ACE2 gene|ACE2
32. SERPINA1 wt Allele|SERPINA1 CAUSES Autophagy
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
CAUSES
Object
Autophagy
33. Coronavirus Infections CAUSES Middle East Respiratory Syndrome
Subject
Coronavirus Infections
Predicate
CAUSES
Object
Middle East Respiratory Syndrome
34. Anti-Inflammatory Agents STIMULATES NF-kappa B
Subject
Anti-Inflammatory Agents
Predicate
STIMULATES
Object
NF-kappa B
35. SERPINA1 wt Allele|SERPINA1 INHIBITS Leukocyte Elastase
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
INHIBITS
Object
Leukocyte Elastase
36. Serine Endopeptidases AFFECTS Acute Lung Injury
Subject
Serine Endopeptidases
Predicate
AFFECTS
Object
Acute Lung Injury
37. SERPINA1 wt Allele|SERPINA1 INHIBITS ADAM17 Protein|ADAM17
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
INHIBITS
Object
ADAM17 Protein|ADAM17
38. ACE2 gene|ACE2 INHIBITS Bradykinin
Subject
ACE2 gene|ACE2
Predicate
INHIBITS
Object
Bradykinin
39. Bradykinin CAUSES Increased capillary permeability (finding)
Subject
Bradykinin
Predicate
CAUSES
Object
Increased capillary permeability (finding)
40. Ability ASSOCIATED_WITH COVID-19
Subject
Ability
Predicate
ASSOCIATED_WITH
Object
COVID-19
41. SERPINA1 wt Allele|SERPINA1 INHIBITS thrombin
Subject
SERPINA1 wt Allele|SERPINA1
Predicate
INHIBITS
Object
thrombin
42. Venous Thromboembolism COEXISTS_WITH COVID-19
Subject
Venous Thromboembolism
Predicate
COEXISTS_WITH
Object
COVID-19
43. Microthrombus COEXISTS_WITH COVID-19
Subject
Microthrombus
Predicate
COEXISTS_WITH
Object
COVID-19
44. DNA INHIBITS Elastases
Subject
DNA
Predicate
INHIBITS
Object
Elastases
45. Histones INHIBITS Elastases
Subject
Histones
Predicate
INHIBITS
Object
Elastases
46. Peptide Hydrolases INHIBITS Elastases
Subject
Peptide Hydrolases
Predicate
INHIBITS
Object
Elastases
47. Syndrome DISRUPTS endothelial cell apoptotic process
Subject
Syndrome
Predicate
DISRUPTS
Object
endothelial cell apoptotic process
48. Acute Lung Injury DISRUPTS endothelial cell apoptotic process
Subject
Acute Lung Injury
Predicate
DISRUPTS
Object
endothelial cell apoptotic process
49. Antiphospholipid Antibodies AUGMENTS Pre-Eclampsia
Subject
Antiphospholipid Antibodies
Predicate
AUGMENTS
Object
Pre-Eclampsia
50. Antiphospholipid Antibodies AUGMENTS COVID-19
Subject
Antiphospholipid Antibodies
Predicate
AUGMENTS
Object
COVID-19
51. Present COEXISTS_WITH Disease
Subject
Present
Predicate
COEXISTS_WITH
Object
Disease
52. alpha 1-Antitrypsin Deficiency PROCESS_OF Patients
Subject
alpha 1-Antitrypsin Deficiency
Predicate
PROCESS_OF
Object
Patients
ABSTRACT
No definitive treatment for COVID-19 exists although promising results have been reported with remdesivir and glucocorticoids. Short of a truly effective preventive or curative vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate COVID-19. We posit at least seven different mechanisms by which AAT may alleviate COVID-19. First, AAT is a serine protease inhibitor (SERPIN) shown to inhibit TMPRSS-2, the host serine protease that cleaves the spike protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of COVID-19. Fourth, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially injurious neutrophils and implicated in acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of bradykinin, reducing the ability of bradykinin to cause a capillary leak in COVID-19. Fifth, AAT inhibits thrombin, and venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in COVID-19. Sixth, AAT inhibition of elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived DNA, histones, and proteases, and implicated in the immunothrombosis of COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated acute lung injury, multi-organ dysfunction, and pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-phospholipid antibodies are increased in both COVID-19 and non-COVID pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat COVID-19 and should be studied.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Alpha 1-Antitrypsin / COVID-19 / Models, Biological Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: Med Hypotheses Year: 2021 Document Type: Article Affiliation country: J.mehy.2020.110394

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Alpha 1-Antitrypsin / COVID-19 / Models, Biological Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: Med Hypotheses Year: 2021 Document Type: Article Affiliation country: J.mehy.2020.110394