IS BRADYKININ INVOLVED IN COVID-19 PATHOGENESIS?

March 18, 2022

INFLAMMATION 

One of the hallmarks of Covid-19 disease is inflammation, mediated in part by overproduction of inflammatory cytokines. However, the mechanisms of such inflammatory process have not been clearly understood. In the past year the potential role of bradykinin, a small peptide and a members of family kinins, in the pathogenesis of COVID19 has been raised. These peptides play a variety of important physiologic roles, including regulation of blood pressure, vascular permeability, inflammation, and blood coagulation. They are produced as a precursor polypeptide and processed by various proteolytic enzymes into their active forms, which then bind to cell surface receptors, thus eliciting the downstream activities of the bradykinin family. Their pro-inflammatory and -coagulative activities make it easy to suspect that they may play a role in severe outcome of Covid-19. What is the evidence?

BRADYKININ RELATED MUTATIONS 

In this context, it is useful to consider types I and II hereditary angioedema, in which either of two types of mutations results in overproduction of bradykinin. This, in turn, results in activation and dysregulation of inflammatory innate immune mechanisms and causes angioedema in tissues, such as the gastrointestinal tract and the larynx.

Several reports have suggested that overexpression of bradykinin can lead to inappropriate immune responses and contribute to SARS-CoV-2 pathogenesis. A study of gene expression in single alveolar cells, a target of SARS-CoV2 infection, has shown that they co-express ACE2 (the viral receptor), kinin (the precursor to the bradykinins), and kallikrein (an enzyme converting kinins to bradykinin). In general, the SARS-CoV-2 infection causes internalization of ACE2, and, subsequently reduces degradation of bradykinin by the internalized ACE2 . As a result, its sequestration could further raise bradykinin levels. Another study has determined the types of upregulated genes in bronchoalveolar lavage fluid from Covid-19 patients. The identified genes were those involved in bradykinin expression and activity, including kallikrein, bradykinin itself, and both bradykinin receptors. The pattern of expression was atypical, and predicted elevation of bradykinin levels and activities, consistent with many of the symptoms associated with Covid-19, including vasodilation, hypotension, vascular permeability and inflammation. This has led to hypothesize that severe cases of Covid-19 could be the result of a “bradykinin storm” and not only a “cytokine storm”. In fact, the two hypotheses do not appear to be mutually exclusive. It should be emphasized that the involved systems are very complex. Further comprehensive clinical studies need to be conducted.

TREATMENT STUDY

An obvious question is whether pharmacologic intervention in bradykinin activities would be of clinical benefit in Covid-19 patients. There has been so far only one study based on a limited number of patients using a bradykinin B2 receptor antagonist, icatibant, which yielded some success in treating patients with Covid-19 . The study involved 9 treated patients, with 18 controls given standard of care. Eight of the 9 treated patients experienced a reduction in required oxygen supplementation, whereas only 3 of the 18 controls showed a similar reduction in the need for oxygen supplementation. However, in 3 of the treatment patients, the need for oxygen returned after cessation of icatibant treatment. Although the size of this study was small and lacked randomized controls, the results seem worthy of further efforts.

CONCLUSION

There have not been subsequent reports implicating bradykinin dysregulation as a driver of Covid-19 severity. This suggests that confirmatory data has not emerged, but its involvement seems to remain an intriguing possibility. Certainly, further well-designed clinical studies and trials might lead to the identification of innovative therapeutics for treating Covid-19 as well as patients with long Covid.

References

  1. Marceau, F. and D. Regoli, Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov, 2004. 3(10): p. 845-52.
  2. Kaplan, A.P. and K. Joseph, Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway. Adv Immunol, 2014. 121: p. 41-89.
  3. Sidarta-Oliveira, D., et al., SARS-CoV-2 receptor is co-expressed with elements of the kinin-kallikrein, renin-angiotensin and coagulation systems in alveolar cells. Sci Rep, 2020. 10(1): p. 19522.
  4. Ou, X., et al., Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun, 2020. 11(1): p. 1620.
  5. Garvin, M.R., et al., A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. Elife, 2020. 9.
  6. Wilczynski, S.A., et al., A Cytokine/Bradykinin Storm Comparison: What Is the Relationship Between Hypertension and COVID-19? Am J Hypertens, 2021. 34(4): p. 304-306.
  7. van de Veerdonk, F.L., et al., Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19. JAMA Netw Open, 2020. 3(8): p. e2017708.

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