Plasminflammation—An Emerging Pathway to Bradykinin Production

Abstract

Plasminogen activation is essential for fibrinolysis—the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.

Measurement of Bradykinin Formation and Degradation in Blood Plasma: Relevance for Acquired Angioedema Associated With Angiotensin Converting Enzyme Inhibition and for Hereditary Angioedema Due to Factor XII or Plasminogen Gene Variants

“…The formation of immunoreactive BK (that includes Lys-BK) induced by contact system activation or by recombinant tissue kallikrein (KLK-1) did not differ between the 2 groups. This line of evidence combines with others to support the hypothesis that plasmin has an active role in the pathogenesis of HAE-C1-INH attacks ( 22 ). In the present work, we quantified the half-life (t 1/2 ) of BK in plasma samples as influenced by an ACE inhibitor added in vitro or administered in vivo to show the transient nature of BK accumulation; this has also relevance to the physiopathology of ACE inhibitor-induced AE.…”

Plasminogen glycoforms alteration and activation susceptibility associated with the missense variant p.Lys330Glu in HAE‐PLG patients

“…FP was recipient of a PhD fellowship from EFS APR2016. Faidra Parsopoulou 1,2,3 Delphine Charignon 4 Maud Tengo 4 Fotis Psarros 5…”

“…Coen Maas 6 Teresa Gonzalez-Quevedo 7 Christian Drouet 3,8 Anastasios E. Germenis 1,2 Accumulating evidence suggests that both IL-1β and IL-17A are crucially involved in IVIG resistance in KD patients. [1][2][3][4][5][6] We previously demonstrated that IVIG could specifically and completely suppress TNF-α-induced, but not IL-1β-induced, protein production of such KD-related cytokines as IL-6 and G-CSF by HCAECs. 7 Furthermore, the dramatic and specific anti-inflammatory effects of IVIG were associated with complete inhibition of C/EBP activity.…”

Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection

“…[18][19][20] This shows that plasmin-dependent bradykinin production is regulated by ACE activity. 21 It is possible that a similar mechanism, linking the fibrinolytic system and the plasma contact system, drives bradykinin production in COVID-19 and enhances pathology. 21 Although most bradykinin is directly degraded (►Fig.…”

“…21 It is possible that a similar mechanism, linking the fibrinolytic system and the plasma contact system, drives bradykinin production in COVID-19 and enhances pathology. 21 Although most bradykinin is directly degraded (►Fig. 1), around 11% of bradykinin is converted (62 AE 10 nmolÁminute À1 ÁmL À1 ) into des-Arg 9 -bradykinin by carboxypeptidase M or N. In comparison with bradykinin, the half-life of des-Arg 9 -bradykinin is at least 10-fold higher (643 AE 436 seconds).…”