Mechanism of BK inducing pulmonary edema and potential drugs. (2002). (2020a). Pulmonary Edema in COVID-19: Explained by Bradykinin?. doi:10.1164/rccm.200905-0665OC, Bull, M. B., and Laragh, J. H. (1968). Cmp 6 (1), 1327. Ann. 8 (5), 475481. Res. Science 367 (6485), 14441448. 11. Not everyone gets side effects. COVID-19 vaccine-related interstitial lung disease: a case study Response of Thiazide-Induced Hypokalemia to Amiloride. (2020). Papi A, Stapleton RD, Shore PM, Bica MA, Chen Y, Larbig M, Welte T. Lung. Front Pharmacol. Neurosci. (2020b). (2019). 7 (4). The activities of the molecules in RAS are ruled by dynamic changes responding to an injury. Br. 313 (5), L845L858. It's normal to experience side effects after a vaccine. J. Physiology-Lung Cell Mol. It has been reported that transepithelial ion transport in alveolar monolayers can be activated by K+ channel openers in vitro under physiological conditions (Leroy et al., 2006). Res. (2020). Am J Physiol Lung Cell Mol Physiol. Antiviral Res. Further studies may determine if CD44 inhibitors can be of use to in COVID-19. Meanwhile, the number of patients in the treatment group presenting improved PaO2/FiO2 and ROX index was higher than that of the control group (95.2% vs. 68.4% and 73.7%). The spike (S) protein of coronavirus, one of the surface glycoproteins, is divided into two functional units, S1 and S2. doi:10.1111/joim.13091, Passi, A., Negrini, D., Albertini, R., de Luca, G., and Miserocchi, G. (1998). J. Cel Physiol 235 (12), 95109523. TRPA1 Agonists Evoke Coughing in guinea Pig and Human Volunteers. BMJ 369, m1432. Pulmonary edema - Symptoms and causes - Mayo Clinic doi:10.1164/rccm.200508-1302OC, Pickkers, P., Dormans, T. P. J., Russel, F. G. M., Hughes, A. D., Thien, T., Schaper, N., et al. K+ Channels Regulate ENaC Expression via Changes in Promoter Activity and Control Fluid Clearance in Alveolar Epithelial Cells. ACIP reviews data. Crit. As the infection progresses, the immune function is impaired, causing damage to multiple organs, additional complications, and eventually death (Yang et al., 2020). Systems Pharmacological Study Illustrates the Immune Regulation, Anti-infection, Anti-inflammation, and Multi-Organ protection Mechanism of Qing-Fei-Pai-Du Decoction in the Treatment of COVID-19. 318 (4), L723L741. These proteins include ion channels (Na channel, K channel and TRPV4), aquaporins (AQP), renin angiotensin system (RAS) proteins, and bradykinin/hyaluronic acid-related enzymes. 92 (6), 693697. Pharmacol. This buildup of fluid leads to shortness of breath. CFTR inhibitors, like glibenclamide and CFTRinh-172 inhibitor, distinctly reduced absorptive alveolar fluid transport (Solymosi et al., 2013). 117 (3), 773783. (2020). Diagnosing COVID-19: The Disease and Tools for Detection. Pathophysiology and incidence - Vaccine-induced immune thrombotic thrombocytopenia (VITT) is an extremely rare syndrome that can occur in individuals who received certain adenoviral-vectored coronavirus disease 2019 (COVID-19) vaccines. doi:10.1001/jama.2020.1585, Wang, Q. Y., Liang, W., Jiang, C., Li, N. Y., Xu, H., Yang, M. N., et al. Cel Mol Biol 20 (5), 10281040. -. Impaired Breakdown of Bradykinin and its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection. Treatment of Pulmonary Edema by ENaC Activators/Stimulators. doi:10.1073/pnas.96.5.2514, Chow, Y.-H., Wang, Y., Plumb, J., O'Brodovich, H., and Hu, J. The site is secure. 291 (6), L1207L1219. doi:10.1161/01.RES.0000247065.11756.19, Andr, E., Gatti, R., Trevisani, M., Preti, D., Baraldi, P., Patacchini, R., et al. The condition presents itself as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and alveolar edema (Xu et al., 2020; Wiersinga et al., 2020). Adult Respiratory Distress Syndrome. 19 (5), 305306. Some of these TCMs along with their constituent and antiviral and reducing pulmonary edema mechanisms are shown in Table 3. As RAS plays an important role in PFC and AFC, astragaloside IV from Astragalus propinquus is able to protect kidney and respiratory by activating the ACE2-Ang-(17)-Mas pathway in RAS and improving ACE2, Ang-(17), Mas level (Wang et l., 2015; Qu, 2019). 4 Clipboard, Search History, and several other advanced features are temporarily unavailable. Lian-Hua-Qing-Wen capsules significantly affect virus morphology, inhibit the SARS-CoV-2 replication with the IC50 value of 411.2g/ml, reduce pro-inflammatory cytokines production at the mRNA level, and show anti-inflammatory effect in vitro (Runfeng et al., 2020). Remdesivir for the Treatment of Covid-19 - Final Report. doi:10.1007/s11427-020-1637-5, Xu, Y.-H., Dong, J.-H., An, W.-M., Lv, X.-Y., Yin, X.-P., Zhang, J.-Z., et al. As Gabazza et al., (2004) reported, lung fibrosis is linked to decreased mRNA and protein expression of AQP-5 in the lung. doi:10.1002/jcp.28602, Otulakowski, G., Rafii, B., Bremner, H. R., and O'Brodovich, H. (1999). Generalized Edema and Pseudothrombocytopenia After ChAdOx1 nCoV-19 COVID-19 Vaccination: A Case Report Reports of side effects of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasing worldwide. Quantitative mRNA Expression Profiling of ACE 2, a Novel Homologue of Angiotensin Converting Enzyme. Influenza Virus Infection Alters Ion Channel Function of Airway and Alveolar Cells: Mechanisms and Physiological Sequelae. (2020). TGF--induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. Creative Commons Attribution License (CC BY). doi:10.1097/CM9.0000000000000797, Ferner, R. E., and Aronson, J. K. (2020). These supportive approaches have been shown to be beneficial as adjuvant therapies in COVID-19 patients. Keywords: COVID-19: Evaluation and management of adults with - UpToDate doi:10.3109/08923973.2014.968256, Jiang, Y.-x., Dai, Z.-l., Zhang, X.-p., Zhao, W., Huang, Q., and Gao, L.-k. (2015). A., and Cook, D. I. (2000). Lab. Since the inhibition of ENaC induces pulmonary edema formation, targeting ENaC is rational in order to enhance fluid clearance from the alveoli. In addition, natural compounds and TCMs which generally have multiple targets should also be investigated, both in terms of their efficacy and safety. Sci. (2020). Inhalation or infusion of salbutamol, a 2-adrenergic agonist, reduced the incidences of pulmonary edema (Sartori et al., 2002) and was found to be beneficial in ARDS patients (Perkins et al., 2006). doi:10.1038/labinvest.2016.150, Zhang, P. h., Han, J., Cao, F., Liu, Y. j., Tian, C., Wu, C. h., et al. It has been shown that SARS-CoV-2 infects human cells via specific binding of S-protein to angiotensin-converting enzyme 2 (ACE2) (Figure 2 Infection and replication process of SARS-CoV-2) (Xu et al., 2020) and the binding affinity between these two proteins is 1020 times greater than that of SARS-CoV and ACE2 (Yan et al., 2020; Wrapp et al., 2020). The general regulation approaches of AFC. Moreover, lower expression of alveolar Na-K-ATPase promotes pulmonary edema, and when the expression of Na-K-ATPase 1- and 2-subunits decreases, maximal alveolar epithelial fluid clearance is reduced (Looney et al., 2005). Mol. doi:10.1152/ajplung.00376.2005, Li, C., Wang, P., Li, M., Zheng, R., Chen, S., Liu, S., et al. A blocked upper airway causes negative pressure in the lungs from trying to breathe through the blockage. COVID-19 Vaccination-related Lymphadenopathy: What To Be Aware Of (2015). 471 (4), 519532. Artif Intell Med. EM did the language polishing. After getting vaccinated for COVID-19, you might experience some temporary symptoms similar to those you might notice when you get a flu shot, such as a sore, swollen arm where you got the shot. (Engl) 133 (9), 10511056. *Correspondence: Hongyue Ma, hongyuema@njutcm.edu.cn; Edyta Marcon, edyta.marcon@utoronto.ca; Jing Zhou, zhoujing_nj@126.com, Abnormal Lung Humoral Metabolism in COVID-19, Conventional Treatment of Pulmonary Edema in COVID-19 Patients, Putative Drug Targets for Pulmonary Edema in COVID-19 Patients, Natural Compounds and Traditional Chinese Medicines for the Treatment of Pulmonary Edema in COVID-19, https://doi.org/10.3389/fphar.2021.664349, https://www.frontiersin.org/articles/10.3389/fphar.2021.664349/full#supplementary-material, http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml. Direct Vascular Effects of Furosemide in Humans. Efficacy and Safety of Garadacimab in Combination with Standard of Care Treatment in Patients with Severe COVID-19. Am. Chem. It has been shown that the incidence and severity of COVID-19 are closely related to abnormal metabolism of inorganic salts. (2011). Abnormal humoral metabolism is mainly manifested as imbalances of water and electrolytes. Negative-feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-dependent Regulation of Transient Receptor Potential Vanilloid 4. What are the vaccines' side effects? - Mayo Clinic Am. Ready, Set, Fuse! Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective. (1998). Here, we provide a perspective on abnormal lung humoral metabolism of pulmonary edema in COVID-19 patients, review the mechanisms by which pulmonary edema may be induced in COVID-19 patients, and propose putative drug targets that may be of use in treating COVID-19. Since pulmonary edema can be promoted by decreased expression of alveolar Na-K-ATPase (Woods et al., 2015), drugs or compounds which activate the sodium channel and Na-K-ATPase may be putative therapeutics. Comment on "Organprotective Effect of Angiotensinconverting Enzyme 2 and its Effect on the Prognosis of COVID19". J. Ethnopharmacology 265, 113301. doi:10.1016/j.jep.2020.113301, Li, F. (2016). (2020). Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential Front Pharmacol. COVID-19; abnormal lung humoral metabolism; drug; pulmonary edema; syndrome coronavirus 2; traditional Chinese medicine. Second, autopsy results showed no evidence of acute infection or cardiovascular disease in the internal organs. The abnormal humoral metabolism and pulmonary edema contribute to the severity of symptoms and fatality of COVID-19 patients. We are grateful to all of the colleagues who have given critical comments on this work. Epub 2020 Jun 20. Overall, the decreased expression of alveolar Na-K-ATPase, misregulation of sodium, potassium, AQP, and RAS channels and abnormal metabolism of BK and HA can all lead to lung liquid clearance failure and pulmonary edema, resulting in severe lung damage and ARDS in COVID-19 patients (Figure 6 The general regulation approaches of AFC). (2014). Aspirin: Generic, Uses, Side Effects, Dosages, Interactions - RxList Millions of people in the United States have received COVID-19 vaccines and they are safe and effective at protecting against COVID-19. The stimulation of TRPA1 can cause coughing, hypersecretion of mucus, rapid shallow breathing as well as bronchoconstriction (Bessac and Jordt, 2008; Birrell et al., 2009), which, if persistent, may cause ARDS and other chronic diseases. However, the activation of matrix metalloproteinases (MMPs), which may be triggered by inflammatory factors (Shapiro, 2001), brings PG degradation, inducing pulmonary edema. Limmer A, Engler A, Kattner S, Gregorius J, Pattberg KT, Schulz R, Schwab J, Roth J, Vogl T, Krawczyk A, Witzke O, Zelinskyy G, Dittmer U, Brenner T, Berger MM. Acad. 158 (6), 16211628. RNA-dependent RNA polymerase (RdRp) is a crucial protease that catalyzes RNA replication from RNA templates and is an appealing therapeutic target.
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