key: cord-0944704-x1ia5wc3 authors: Zwaveling, Suzanne; Gerth van Wijk, Roy; Karim, Faiz title: Pulmonary edema in COVID-19: Explained by bradykinin? date: 2020-09-29 journal: J Allergy Clin Immunol DOI: 10.1016/j.jaci.2020.08.038 sha: e88093d3e6d226155b364a8b93ed01d96cc5020a doc_id: 944704 cord_uid: x1ia5wc3 nan Pulmonary edema in COVID-19: Explained by bradykinin? Q 1 To the Editor: We read with great interest the article by Hosoki et al, 1 which provides an excellent overview of the mechanisms of coronavirus disease 2019 . However, the authors did not discuss the possible role of bradykinin in COVID-19. Severe acute respiratory syndrome coronavirus 2 binds to target cells through the angiotensin-converting enzyme-2 (ACE-2) receptor. 2 These receptors are expressed on epithelial cells of the lung, kidneys, intestine, and blood vessels. 3 Recently, a proposal by Veerdonk et al 4 shed new light on the role of ACE-2 in the pathophysiology of COVID-19 through the kallikrein-kinin system. ACE converts angiotensin I into angiotensin II by the removal of 2 peptides, which induces vasoconstriction and inactivates bradykinin, a known vasodilator. ACE-2 is suggested to counteract ACE in RAS Q 2 by converting angiotensin II into a metabolite, angiotensin 1-7, that leads to vasodilatation by stimulation of nitric oxide synthase. 5 Interestingly, ACE-2 also hydrolyzes the active bradykinin metabolite des-Arg 9 -bradykinin, which normally binds to the bradykinin receptor type 1 (BKB1), which is expressed on endothelial cells in the lungs on bronchiolar exocrine cells and pneumocytes type II. Signaling through the BKB1 receptor can induce fluid extravasation and recruitment of leucocytes to the lungs. 6 Suppression of ACE-2 by severe acute respiratory syndrome coronavirus 2 will impair the inhibition of des-Arg 9 -bradykinin ( ). Consequently, increased activation of BKB1 receptors will lead to extra fluid transversion, which results in pulmonary edema. Lessons from (hereditary or acquired) angioedema show us that activation of the bradykinin type 2 receptor (BKB2) instead of BKB1 by bradykinin itself is considered to be principally responsible for the development of edema Q 3 . 7 Bradykinin is generated through the plasma-contact system, when high-molecular-weight kininogen is cleaved from plasmakallikrein. The binding of bradykinin to the BKB2 receptor on endothelial cells causes active fluid transfer through 3 known mechanisms, which all create vascular pores. The activation of the BKB2 receptor results directly in dissolution of adherens junctions, and also enhances phosphorylation of transmembrane vascular endothelial cadherin molecules, which are then internalized and degraded. The ensuing actin cytoskeleton constriction increases pore size between endothelial cells, with consequent vascular leakage. It is known that engagement of BKB2 by bradykinin can activate BKB1, but the overall role of BKB1 in hereditary angioedema (HAE) is uncertain. Remarkably, the BKB1 receptor is rarely expressed in normal conditions, but proinflammatory cytokines can upregulate the expression of BKB1 on endothelial cells. This suggest that blockage of BKB1 in the inflammatory state should be just as important as blocking BKB2 to prevent edema in COVID-19. To support this theory, it would be interesting to analyze whether bradykinin levels and consequently des-Arg 9 -bradykinin levels are increased in patients with COVID-19. Moreover, if the pathophysiology of pulmonary edema in COVID-19 corresponds with the pathophysiology of HAE, exploring therapeutic options used to treat HAE would be a logical step. Targeting the bradykinin system by either inhibiting bradykinin production or blocking bradykinin receptors may open new therapeutic options to control COVID-19-induced pulmonary edema. Further studies are required to better understand the pathophysiology of this complex disease to invent treatment options for a more adequate response in the future. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 Molecular mechanisms and epidemiology of COVID-19 from an allergist's perspective Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome COVID-19 interactions with angiotensin-converting enzyme 2 (ACE2) and the kinin system: looking at a potential treatment Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration Hereditary angioedema