key: cord-0722080-rwkfev8j
authors: Kaplan, Allen P.; Ghebrehiwet, Berhane
title: Pathways for Bradykinin Formation and Interrelationship with Complement as a Cause of Edematous Lung in COVID-19 Patients
date: 2020-10-28
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2020.10.025
sha: 7b2d7877fa45752bacd8b4d8aa7ba2c6b646de91
doc_id: 722080
cord_uid: rwkfev8j

nan

include dry cough, dyspnea, tachypnea, a feeling of drowning, pulmonary edema, unilateral or 37 bilateral pneumonia, mottling and ground glass opacifies on CT scan, and progression to the 38 Acute Respiratory Distress Syndrome (ARDS) requiring ventilatory support(2). Hypoxemia is 39 particularly prominent throughout and a hyaline membrane of dead cells can be observed at 40 autopsy. Once infection takes hold, a cascade of inflammatory events is initiated including the 41 release of cytokines such as I-1, IL-6, IP-10, MCP-1, TNFα(3) (and many more) which has been 42 referred to as a "cytokine storm". In addition, the prominent edema seen throughout the lung and 43 the association of ACE inhibition with severe angioedema has focused attention on another 44 innate inflammatory cascade; namely, the overproduction of bradykinin(3) which is the focus of 45 this editorial. 46 47 There are two general pathways for the production of bradykinin, the first being the release of 48 cellular tissue kallikrein which cleaves low molecular weight kininogen (LK) to release lys-49 bradykinin (Fig. 1) . Tissue kallikrein is secreted as an active enzyme (i.e. processed 50 intracellularly) and is a particularly prominent product of the lung, pancreas, kidney, salivary 51 glands, and the prostate. There are 15 homologous gene products, three of which can produce 52 bradykinin (KLK 1, 2, and 12), KLK1 being the most prominent. 53 54 J o u r n a l P r e -p r o o f and high-molecular weight kininogen (HK)(4). Prekallikrein circulates primarily as a 56 bimolecular complex with HK (about 75-80% bound) as does coagulation factor XI (95% is 57 bound). They compete for a single overlapping binding site but there is sufficient HK present to 58 bind both. Both factor XII and prekallikrein possess minute levels of proteolytic activity relative 59 to their respective active enzymes which may be the initial spark needed for activation to 60 proceed. All three proteins are also bound to bimolecular sites on the surface of endothelial cells 61 ( Figure 1 ). Factor XII binds primarily to u-PAR-cytokeratin 1 (CK-1) while HK binds to 62 gC1qR-cytokeratin 1 with PK attached to the HK (Fig. 1 ). Once activation proceeds, Factor XII 63 is converted to two forms of the activated enzyme, factor XIIa (80 Kd) and factor XIIf (28.5-30 64

Kd; β FXIIa). Both can convert prekallikrein to kallikrein and kallikrein digests HK to release 65 bradykinin (Arg-pro-pro-gly-phe-ser-pro-phe-arg). Factor XII activation proceeds by a relatively 66 slow autoactivation process to produce a small amount of factor XIIa and a very rapid positive 67 feedback in which the initial kallikrein formed activates all remaining factor XII in seconds to 68 yield factor XIIa and then factor XIIf. Tissue kallikrein does not activate factor XII. The larger 69 80 Kd factor XIIa is the clotting factor that converts factor XI to factor XIa to continue the 70 intrinsic coagulation pathway (Fig. 1 ). Factor XIIf, lacks a surface binding site, loses 96-98% of CoV-2. 79 80 Bradykinin causes vasodilation and increases vascular permeability by interacting with 81 constitutively expressed B-2 receptors on small venules. The same is true of lys-bradykinin 82 produced by tissue kallikrein (Fig. 1) although the lys is rapidly removed by aminopeptidase P. 83

Bradykinin is degraded primarily by ACE, a dipeptidase which removes the C-terminal phe-arg, 84 which inactivates it, followed by removal of ser-pro. An alternative process requires 85 carboxypeptidase activity (carboxypeptidase N in plasma and carboxypeptidase M on pulmonary 86 vascular endothelial cells) to first remove the C-terminal arg from either bradykinin (plasma 87 cascade) or lys-bradykinin (tissue kallikrein product) (Fig. 1) . This leaves des-arg 9 bradykinin 88 (Arg-pro-pro-gly-phe-ser-pro-phe) which is minimally reactive with B-2. However this peptide 89 binds to the B-1 receptor which also mediates vasodilation and vascular permeability. The B-1 90 receptor is not normally present but is induced by IL-1 or TNFα (produced by febrile viral 91 illnesses such as COVID-19) as well as gC1qR. It's ligands are des-arg 9 bradykinin(3) as well as 92 des-arg 9 lys-bradykinin ( Fig. 1) . 93 94 There are many observations and theories regarding a prominent role for bradykinin and perhaps 95 des-arg 9 bradykinin in the pathogenesis of the pulmonary dysfunction of COVID-19 which is 96 linked in part to changes in the renin-angiotensin system (RAS). Studies of gene expression in 97 bronchoalveolar lavage specimens of COVID-19 patients(5), when compared to normal control 98 specimens, reveal upregulation of multiple components that lead to bradykinin production and 99 expression for C1-INH was decreased 33-fold which would render the plasma bradykinin 102 cascade labile and overreactive as we see in C1-INH deficiency (types I and II HAE) in which 103 enzymes not adequately inhibited by C1-INH include both forms of activated factor XII, plasma 104 kallikrein, and C1r. By contrast, gene expression for ACE was decreased 8-fold so that 105 bradykinin would not be inactivated normally. While viral binding to ACE-2 limits its 106 enzymatic activity(3) so that des-arg 9 bradykinin is not degraded (ACE-2 removes C-terminal 107 phe) and lowered ACE levels also limit des-arg 9 bradykinin degradation (it removes C-terminal 108 ser-pro-phe acting then as a tripeptidase rather than a dipeptidase). With the markedly 109 augmented bradykinin receptor production, a "bradykinin storm" can result. 110 111 Our own preliminary observations (unpublished) reveal upregulation and secretion of gC1qR by 112 infected cells which creates the cell surface platform for activation of the bradykinin cascade and 113 secreted gC1qR also upregulates the B-1 receptor(6). The Renin-Angiotensin system(7) can also 114 be contributory in that decreased ACE limits formation of the vasoconstrictor angiotensin II from 115 angiotensin I. As angiotensin I accumulates, ACE-2 removes C-terminal phe to produce 116 angiotensin 1-9. This moiety stimulates angiotensin-2 receptors to cause vasodilation and can do 117 so synergistically with bradykinin(5). If significant amounts of angiotensin II were produced, 118 ACE-2 can then convert it to another vasodilator, angiotensin 1-7 active through the MAS 119 receptor(7). Here, the balance of decreased ACE-2 via viral binding and internalization(3) and 120

increased ACE-2, as seen when COVID-2 BAL fluids are examined(5), needs to be quantified at 121 the protein level (cell surface and interstitial fluid) rather than the DNA level to determine the net 122 enzymatic effect. 123

There are numerous reports of a possible therapeutic role for antagonists of cytokines such as IL-125 1 (Anakinra) or IL-6 (Tocilizumab) to treat COVID-19(2, 7, 8) . We suggest use of lanadelumab 126 to block plasma kallikrein (9) can release HSP-90 and prolylcarboxypeptidase. Both convert PK to plasma kallikrein if PK is

A pneumonia outbreak 138 associated with a new coronavirus of probable bat origin

Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress 143 syndrome

The plasma bradykinin-forming pathways and its 145 interrelationships with complement

A mechanistic model 147 and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

Soluble 150 gC1qR Is an Autocrine Signal That Induces B1R Expression on Endothelial Cells

SARS-CoV-2 as a Factor to Disbalance the Renin-Angiotensin System: A Suspect 154 in the Case of Exacerbated IL-6 Production

COVID-19 as an Acute Inflammatory Disease

Structure-function studies using deletion mutants identify domains of gC1qR/p33 as potential 160 therapeutic targets for vascular permeability and inflammation