Drug Discov. RNA-dependent RNA polymerase (RdRp) is a crucial protease that catalyzes RNA replication from RNA templates and is an appealing therapeutic target. doi:10.1101/2020.03.31.20038935, Yang, R., Liu, H., Bai, C., Wang, Y., Zhang, X., Guo, R., et al. The functional inhibition of relevant lung enzymes and ion channels may disturb AFC, thus resulting pulmonary edema in COVID-19 patients. doi:10.5114/pdia.2013.37040, Cui, M., Gosu, V., Basith, S., Hong, S., and Choi, S. (2016). Cough Reflex Testing with Inhaled Capsaicin and TRPV1 Activation in Asthma and Comorbid Conditions. Fondazione Salvatore Maugeri (IRCCS), Italy. Lipoxin A4 (LXA4) can stabilize the permeability of pulmonary microvascular endothelial cell by regulating the expression of AQP-5 and MMP-9, and reduce alveolar fluid exudation (Shi et al., 2018). (2021). Immunopharmacology and Immunotoxicology 36 (6), 420425. J. Cel Physiol 234 (11), 2005720065. Res. Acad. 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Aspirin is used to reduce fever and relieve mild to moderate pain from conditions such as muscle aches, toothaches, common cold, and headaches.It may also be used to reduce pain and swelling in conditions such as arthritis.Aspirin is known as a salicylate and a nonsteroidal anti-inflammatory drug ().It works by blocking a certain natural substance in your body to reduce pain and swelling. 97 (18), 1028210287. Glucocorticoid-stimulated Lung Epithelial Na(+) Transport Is Associated with Regulated ENaC and Sgk1 Expression. 158, 104850. doi:10.1016/j.phrs.2020.104850, Ma, Q., Qiu, M., Zhou, H., Chen, J., Yang, X., Deng, Z., et al. The frequency and severity of systemic adverse events was higher after dose 2 than dose 1. Pharmacol. Clin. AQP-5 plays a significant role in pulmonary edema and decreased expression of AQP-5 has been observed during the disease process. As Gabazza et al., (2004) reported, lung fibrosis is linked to decreased mRNA and protein expression of AQP-5 in the lung. A., et al. This buildup of fluid leads to shortness of breath. The Add-On Effect of Chinese Herbal Medicine on COVID-19: A Systematic Review and Meta-Analysis. 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). doi:10.1161/01.RES.0000247065.11756.19, Andr, E., Gatti, R., Trevisani, M., Preti, D., Baraldi, P., Patacchini, R., et al. (2006) reported that the cryptotanshinone in Salvia miltiorrhiz can inhibit the synthesis of cGMP and NO in vein endothelial cells, activate NO/cGMP pathway and improve the blood circulation. Therefore, the S protein determines the host cell of the virus, regulates the viral attachment and fusion with the host cell membrane, and promotes cellular invasion. Here, we summarized several natural compounds and TCM formulas which are very likely to be potential drugs or have already shown predominant efficacy of COVID-19 patients. eCollection 2023. Atractylenolide-I, the active component of atractylodes, could minimize the formation of IL-6 and TNF- (Ji et al., 2014), inhibiting the generation of inflammatory cytokines causing inflammatory response, thus lowering the possibility of developing pulmonary edema. Res. Am. (2003). Remdesivir for the Treatment of Covid-19 - Final Report. RAS, especially several cleavage products of the peptide angiotensin (AGT) along with their receptors, maintains a balance of fluid volume and pressure. The spike (S) protein of coronavirus, one of the surface glycoproteins, is divided into two functional units, S1 and S2. FIGURE 1. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Pulmonary edema is an abnormal buildup of fluid in the lungs. doi:10.1152/physrev.1974.54.3.678, Steinritz, D., Stenger, B., Dietrich, A., Gudermann, T., and Popp, T. (2018). (2013). Its active absorption of Na+ is the main driving force of fluid clearance at birth and alveolar fluid absorption at adult stage (Bardou et al., 2012). After internal reviews of the reports, the CDC "did not find any data suggesting a link between Covid-19 vaccines and tinnitus," an agency . (2020). 1480 (1), 73103. Hormonal Regulation and Genomic Organization of the Human Amiloride-Sensitive Epithelial Sodium Channel Subunit Gene. It promotes the clearance of surplus fluid in alveoli and keeps alveolar space dry (Wittekindt and Dietl, 2019). Further studies may determine if CD44 inhibitors can be of use to in COVID-19. Authors Mabrouk Bahloul 1 . Physiol. Med. TABLE 1. doi:10.1152/physiol.00026.2008, Birket, S. E., Chu, K. K., Houser, G. H., Liu, L., Fernandez, C. M., Solomon, G. M., et al. SN Compr. J. Pharmacol. Impaired Breakdown of Bradykinin and its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection. Some of these TCMs along with their constituent and antiviral and reducing pulmonary edema mechanisms are shown in Table 3. These proteins include ion channels (Na channel, K channel and TRPV4), aquaporins (AQP), renin angiotensin system (RAS) proteins, and bradykinin/hyaluronic acid-related enzymes. In the meantime, we urgently need potent reduction in fatality of COVID-19. Thus, promoting the degradation of HA may be significant in the recovery process. (2021). 2021 May 7;8:644678. doi: 10.3389/fmed.2021.644678. Pharmaceuticals 13 (9), 259. doi:10.3390/ph13090259, Ren, J.-l., Zhang, A.-H., and Wang, X.-J. However, the efficacy and safety of these drugs in COVID-19 patients are unclear. BMJ 369, m1432. medRxiv. Optimizing Diagnostic Strategy for Novel Coronavirus Pneumonia, a Multi-center Study in Eastern China. The cystic fibrosis transmembrane conductance regulator (CFTR) and the ENaC located in the airway apical membranes and alveolar epithelial cells are essential in regulating lung fluid balance across airway as the chloride (Cl) and bicarbonate (HCO3) secretion conduits, and alveolar epithelia by sodium (Na+) ion absorption (Matalon, 1999; Birket et al., 2016; Londino et al., 2017). (2010). Respir. doi:10.1161/01.RES.0000125623.56442.20, Nayler, W., and Dillon, J. Sci. 11 (1), 65. doi:10.1186/1465-9921-11-65, Han, J., Li, H., Bhandari, S., Cao, F., Wang, X. Y., Tian, C., et al. doi:10.1038/s12276-018-0075-4, Zwaveling, S., Gerth van Wijk, R., and Karim, F. (2020). Quantitative mRNA Expression Profiling of ACE 2, a Novel Homologue of Angiotensin Converting Enzyme. Clinical Course and Outcomes of Critically Ill Patients with SARS-CoV-2 Pneumonia in Wuhan, China: a Single-Centered, Retrospective, Observational Study. 274, L203L211. Among all vaccine recipients, 66.6% reported at least one systemic reaction in the 7 days after vaccination. 2020. 275 (2), L414L422. Acta (Bba) - Biomembranes 1818 (7), 16821690. (2014). doi:10.1007/s00210-014-1058-1, Grant, R. A., Morales-Nebreda, L., Morales-Nebreda, L., Markov, N. S., Swaminathan, S., Querrey, M., et al. 10.1111/nyas.14472 This condition is generally referred to as pulmonary edema and is a direct consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The Study on the Treatment of Xuebijing Injection (XBJ) in Adults with Severe or Critical Corona Virus Disease 2019 and the Inhibitory Effect of XBJ against SARS-CoV-2. 99 (9), 988995. Coronavirus Disease 2019 Treatment A Review of Early and Emerging Options. Amiloride. Thromb. doi:10.1007/s11596-015-1490-6, Jovanovi, S., Crawford, R. M., Ranki, H. J., and Jovanovi, A. J. When there, the virus itself and virus-mediated protein-protein interactions lead to the lung inflammatory storm responsible for the observed increasing vascular permeability in lung and pulmonary edema (Tang et al., 2020). (2001). 289 (1), L104L110. Br. This may be due to lingering inflammation and other factors. The Role of Proteoglycans in Pulmonaryedema Development. DD&T 14 (5), 256258. A blocked upper airway causes negative pressure in the lungs from trying to breathe through the blockage. Am J Physiol Lung Cell Mol Physiol. CFTR and NKCC inhibitors show promise in treating pulmonary edema. Thus, it could be a potential RdRp inhibitor for SARS-CoV-2 (Lung et al., 2020). Currently, only icatibant has been approved as bradykinin antagonist for clinical treatment, and relevant studies have revealed that cefepime, cefpirome, imatinib, raloxifene, sildenafil, ponatinib, abemaciclib and entrectinib may also act as prospective non-selective bradykinin antagonists and have potential for treatment of COVID-19 (Rasaeifar et al., 2020). 288 (2), 192206. Electrolyte Imbalances in Patients with Severe Coronavirus Disease 2019 (COVID-19). -, Ahmed M. H., Hassan A. Jiangsu Qing Lan Project for Young Academic Leaders of China. ACE2 is most abundantly expressed in human vascular endothelial cells as well as alveolar and intestinal epithelial cells. doi:10.1016/s2213-2600(20)30225-3, Goldenberg, N. M., Ravindran, K., and Kuebler, W. M. (2015). Anti-hypertensive Angiotensin II Receptor Blockers Associated to Mitigation of Disease Severity in Elderly COVID-19 Patients. FOIA doi:10.1530/EJE-20-0338, Clapham, D. E., Runnels, L. W., and Strbing, C. (2001). The activation of -adrenergic receptor, especially 2 (Mutlu et al., 2004), was found to stimulate Na+ and fluid reabsorption. Phytomedicine 85, 153282. doi:10.1016/j.phymed.2020.153282, Ma, Q., Pan, W., Li, R., Liu, B., Li, C., Xie, Y., et al. (2020e). Received: 05 February 2021; Accepted: 25 May 2021;Published: 07 June 2021. doi:10.1146/annurev-virology-110615-042301, Li, L., Zhang, W., Hu, Y., Tong, X., Zheng, S., Yang, J., et al. 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. Drugs targeting at least some of these proteins have already existed and could be repurposed to manage pulmonary edema seen in SARS-COV-2 infections. We observed a case of a delayed local reaction in a 38-year-old woman who had received the first dose of the BNT162b2 vaccine. Symptoms that are common to all of these conditions include cough and shortness of breath. (2020). Sci. Lancet Respir. MeSH Prc, N. H. C. o. t. (2020). 2 3 Postauthorisation reports of severe reactions, including anaphylaxis, have been extremely rare, occurring in only 4.5 reported cases per million doses. However, palpable lymphadenopathy commonly involving the axilla as an immune response to vaccination may present a clinical diagnostic dilemma especially in persons with . 383, 23332344. Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on 2 -Adrenergic Receptor Signaling. (1999). Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized with COVID-19 in the New York City Area. COVID-19 can cause lung complications such as pneumonia and, in the most severe cases, acute respiratory distress syndrome, or ARDS . includes glycoproteins, membranes and nucleic acids. Specific Pharmacology of Calcium in Myocardium, Cardiac Pacemakers, and Vascular Smooth Muscle. Other anti-viral drugs, such as arbidol, chloroquine phosphate and ritonavir, did not exhibit efficacy in randomized, placebo-controlled trials in COVID-19 patients. (2016). (2012). (1997). Comment on "Organprotective Effect of Angiotensinconverting Enzyme 2 and its Effect on the Prognosis of COVID19". Circ. Negative-feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-dependent Regulation of Transient Receptor Potential Vanilloid 4. Pulmonary capillary leak syndrome following COVID-19 virus infection. Transient Receptor Potential Channels in Pulmonary Chemical Injuries and as Countermeasure Targets. doi:10.1152/ajplung.1998.275.3.L631, Perkins, G. D., McAuley, D. F., Thickett, D. R., and Gao, F. (2006). Technol. Chemical Composition and Pharmacological Mechanism of Qingfei Paidu Decoction and Ma Xing Shi Gan Decoction against Coronavirus Disease 2019 (COVID-19): In Silico and Experimental Study. Cepharanthine, a bisbenzylisoquinoline alkaloid derived from tubers of Stephania Japonica, was shown to have a wide-spectrum inhibitor of pan--coronavirus (Fan et al., 2020; Rogosnitzky et al., 2020). Front. Preprint. COVID-19; abnormal lung humoral metabolism; drug; pulmonary edema; syndrome coronavirus 2; traditional Chinese medicine. medRxiv. (2020c). Cel Mol Biol 54 (3), 370383. Cell. Invest. In early April 2021, an 86-year-old man presented to the emergency department with a 1-day history of weakness, dyspnoea and fever. 2020 Aug 14;15(1):103. doi: 10.1186/s13000-020-01017-8. Respir. HA is a polysaccharide existing in most connective tissues which can trap approximately 1,000 times its weight in water and form hydrogel. 34, 101658. doi:10.1016/j.tmaid.2020.101658. doi:10.1111/j.1365-2125.1986.tb02859.x, Negrini, D., Passi, A., de Luca, G., and Miserocchi, G. (1998). Evidences for TRPs as medium of lung injury are emerging from studies on various inhalational chemical threats (Achanta and Jordt, 2020). Dexmedetomidine Alleviates Pulmonary Edema by Upregulating AQP1 and AQP5 Expression in Rats with Acute Lung Injury Induced by Lipopolysaccharide. LipoxinA4 Attenuates Acute Pancreatitis-Associated Acute Lung Injury by Regulating AQP-5 and MMP-9 Expression, Anti-apoptosis and PKC/SSeCKS-mediated F-Actin Activation. 2023 Apr;201(2):159-170. doi: 10.1007/s00408-023-00615-9. Res. It shows the vaccine is teaching your body's immune system how to protect itself from the disease. The secretion of alveolar fluid, caused by inhibiting Na+ entry, is sensitive to inhibition of CFTR, NKCC, or Na+-K+-ATPase (Solymosi et al., 2013), suggesting that CFTR, NKCC or Na+-K+-ATPase inhibitors may have potential in treating pulmonary edema caused by low expression of ENaC. This is supported by the studies of AQP-5 deficient mice where a fibrotic phenotype with increased deposition of extracellular collagen type I was observed in thickened alveolar walls (Gabazza et al., 2004). Most of the published data about this association come from case reports and series. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. doi:10.1056/NEJMoa2007764, Bessac, B. F., and Jordt, S.-E. (2008). Physiol. 35 (5), 684688. An official website of the United States government. Matrix Proteinases in Lung Biology. Pain at the injection site had completely resolved within 2 days. doi:10.1161/01.cir.96.6.1847. J. Appl. The Lancet 395 (10223), 497506. 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. doi:10.1007/s43440-020-00132-z, Runfeng, L., Yunlong, H., Jicheng, H., Weiqi, P., Qinhai, M., Yongxia, S., et al. Traditional Chinese Medicine for COVID-19 Treatment. HA is synthesized by HAS2. doi:10.1056/NEJMoa2028836, Tang, Y., Liu, J., Zhang, D., Xu, Z., Ji, J., and Wen, C. (2020). (2019). 8 (5), 475481. Some patients also have leucopenia and lymphopenia, suggesting a weak immune function, and high prothrombin time and D-dimer level, indicating abnormal blood clotting function (Wang et al., 2020), which can all lead to lung damage and the severer pulmonary edema. J. Biol. Na+/K+-ATPase and ion channels (sodium, potassium, AQPs, and TRPs) are all involved in the regulation of AFC. Diagn Pathol. doi:10.1152/ajplung.00078.2015, Wsten-van Asperen, R. M., Lutter, R., Specht, P. A., Moll, G. N., van Woensel, J. doi:10.1111/bph.12414, Kaur, S. P., and Gupta, V. (2020). Existing drugs and inhibitors targeting the components of humoral metabolism may serve as potential treatments for COVID-19 and should be further investigated. Nervous system conditions or surgeries. Toxin means various pathogenic microorganism and inflammatory storm presenting in infected patients, and dampness means the abnormal humoral metabolism like inflammatory exudation. Abnormal humoral metabolism is mainly manifested as imbalances of water and electrolytes. SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis. Who (2021). As of Sunday, at least 16,183 people had filed complaints with the Centers for Disease Control and Prevention that they'd developed tinnitus, or ringing in their ears, after receiving a Covid vaccine. TGF--induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. Clinical Characteristics of Coronavirus Disease 2019 in China. Zhang J, Zhou N, Wang Y, Liu T, Cao Y, Feng W, Zheng X. Influenza Induces IL-8 and GM-CSF Secretion by Human Alveolar Epithelial Cells through HGF/c-Met and TGF-/EGFR Signaling. So far, only remdesivir was approved by FDA for the compassionate use in severe infected COVID-19 patients (Beigel et al., 2020). (Engl) 133 (9), 10511056. Emodin, an anthraquinone compound from genus Rheum and Polygonum, can markedly prevent the binding of S protein and ACE2 in the study of SARS-CoV (Ho et al., 2007). Physiology 23, 360370. Most side effects are mild and normally last only a day or two. Rev. Abnormal humoral metabolism is mainly manifested as imbalances of water and electrolytes. J. Respir. Elevated pulmonary venous pressure leads to faster fluid infiltration into the interstitial lung than the ability of the pulmonary lymphatic vessel to drain away fluid, resulting in pulmonary edema. Also, thrombocytopenia and thrombosis have been mostly reported after AstraZeneca (ChAdOx1 nCoV-19) and Johnson & Johnson/Janssen COVID-19 vaccines [ 3 ]. J. Med. It has been revealed that COVID-19 patients treated with Lian-Hua-Qing-Wen capsules for 14days resulted in a considerably higher recovery rate of 91.5%, a dramatically shorter median time to symptom recovery of 7days than the control group, which applied conventional treatment (Hu et al., 2021). National Library of Medicine TABLE 2. The expression of AQP-5 is regulated by inflammatory cytokines, like TNF-, elevated in the plasma of critical COVID-19 patients (Hui and Zumla, 2019). Moreover, exogenous delivery of Ang (17) was shown to play a part in reducing inflammation and improving pulmonary function in ARDS models (Wosten-van Asperen et al., 2011). Exp. Millions of people in the United States have received COVID-19 vaccines and they are safe and effective at protecting against COVID-19. Role of Drugs Used for Chronic Disease Management on Susceptibility and Severity of COVID19: A Large CaseControl Study. Coronavirus; Race and Medicine . Acad. Eur. Is Amiloride a Promising Cardiovascular Medication to Persist in the COVID-19 Crisis?. Science 367 (6483), 12601263. doi:10.1152/ajplung.00373.2014, Hu, F., Chen, J., Chen, H., Zhu, J., Wang, C., Ni, H. B., et al. With the presence of active basolateral Na+-K+-ATPase, inhibition of the entry of apical Na+ can generate a concentration gradient inducing the uptake of basolateral Na+ with Cl by Na+-K+-2Cl cotransporter (NKCC) and thus induce the apical secretion of Cl (Solymosi et al., 2013). First post-authorization U.S. doses of Janssen COVID -19 Vaccine. Sodium transport is the main ion transport involved in the AFC. Pulmonary Edema in COVID-19: Explained by Bradykinin?. 2021 Jan;93(1):94-96. doi: 10.1002/jmv.26152. Original Article Antibody Responses to Haemophilus influenzae Type b Vaccines in Men with Human . doi:10.1165/rcmb.2002-0101OC, Kaneko, Y., and Szallasi, A. (2020a). Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Allergol. (2009). 274 (18), 1243112437. doi:10.1001/jama.2020.10044, Lippi, G., South, A. M., and Henry, B. M. (2020). FIGURE 6. (1977). Am. (2006). Inflammatory cytokines and inflammatory storm in COVID-19 patients can strongly induce the expression of HA-synthase-2 (HAS2), while hyaluronidase level decreases, resulting in the accumulation of HA and inducing ARDS and pulmonary edema (Shi. (2014). Currently, no specific drug has been developed to against COVID-19, although some existing drugs have been repurposed and approved for treating hospitalized patients (Ferner and Aronson, 2020; Schlagenhauf et al., 2020). COVID-19, an infectious disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a global reach. Resolving D1 (Wang et al., 2014), generated from -3 fatty docosahexaenoic acids, and ursodeoxycholic acid (Niu et al., 2019) can stimulate AFC and Na-K-ATPase in LPS-induced pulmonary edema via alveolar epithelial sodium channel and ALX/cAMP/PI3K pathway, respectively. Viruses 4 (4), 557580. Rev. Sharma, A., Garcia, G., Wang, Y., Plummer, J. T., Morizono, K., Arumugaswami, V., et al. 3 (1), 237261. (2015). 6, 331345. Perplexingly, successful balance of lung humoral metabolism may lead to the reduction of the number of COVID-19 death limiting the possibility of healthcare services with insufficient capacity to provide ventilator-assisted respiration. When SARS-COV-2 invades, vascular endothelial cells are damaged, causing insufficient arterial flow and minimal thrombus. (1999). The toad venom injection can significantly improve the pulmonary function of COVID-19 patients by regulating PaO2/FiO2 and ROX index and thus alleviate pulmonary edema. Thorax 69 (1), 4654. (2008). (2020). Am. Studies have confirmed that selective TRPV4 activation induces rapid loss of alveolo-capillary barrier function and consequent alveolar edema formation (Alvarez et al., 2006). Mol. Physiol. The imbalance of fluid metabolism, pulmonary fluid clearance (PFC) and rich-protein fluid entrance, may be a key reason for the acute exacerbation of pulmonary edema in COVID-19 patients. doi:10.1126/scitranslmed.3004276, Towne, J. E., Krane, C. M., Bachurski, C. J., and Menon, A. G. (2001). (1986). (2020b). 2020 Mar 23:3558887. doi: 10.2139/ssrn.3558887. Ann. The Neutrophil-To-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19. It is known that SARS-CoV-2 invades human cells by binding angiotensin-converting enzyme-2 (ACE-2) receptor and other membrane ectopeptidases (Xu et al., 2020). doi:10.3109/08923973.2014.968256, Jiang, Y.-x., Dai, Z.-l., Zhang, X.-p., Zhao, W., Huang, Q., and Gao, L.-k. (2015). Please enable it to take advantage of the complete set of features! Ann. *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. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. Biophys. Alternative Names Lung congestion; Lung water; Pulmonary congestion; Heart failure - pulmonary edema Causes Pulmonary edema is often caused by congestive heart failure. Pharmacol. Cel Rep. Med. (2020a). Circulation 37 (1), 4553. Pathological Findings of COVID-19 Associated with Acute Respiratory Distress Syndrome. (2020). Int. Physiol. doi:10.5582/ddt.2020.03070, Ahmed, M. H., and Hassan, A. 96 (5), 25142519. 157, 104882. doi:10.1016/j.phrs.2020.104882, Zhang, H., and Baker, A. Structure, Function, and Evolution of Coronavirus Spike Proteins. Creative Commons Attribution License (CC BY). Fedratinib, an FDA approved JAK2 inhibitor, may be used to reduce the mortality associated with hyperinflammation by suppressing the production of several Th17 cytokines (i.e., IL1b and TNF-alpha, IL21, IL22, IL17) and the formation of pulmonary edema in combination with anti-viral drugs (Yang et al., 2020e). Virol. COVID-19 can cause blood clots, even months after diagnosis. Int. doi:10.1074/jbc.274.53.37834, De Logu, F., Patacchini, R., Fontana, G., and Geppetti, P. (2016). (2021). A recent review has summarized the effects of TRPs in pulmonary chemical injuries, which includes the representative TRPA1, TRPV1 and TRPV4 antagonists which have participated in preclinical and clinical studies (Achanta and Jordt, 2020) (Supplementary Tables S1S3). Antiviral Res. (2021). Res. 171 (10), 24742507. Cel Mol Biol 28 (3), 363372. Physiol. CDC interim clinical considerations and FDA Front. Annu. Further, ARDS is sometimes initially diagnosed as pneumonia or pulmonary edema (fluid in the lungs from heart disease). doi:10.1073/pnas.96.5.2514, Chow, Y.-H., Wang, Y., Plumb, J., O'Brodovich, H., and Hu, J. Some natural compounds along with their antiviral and reducing pulmonary edema mechanisms are shown in Table 2. Am. doi:10.1136/bmj.m1432, Fleckenstein, A. doi:10.1101/2020.03.02.20029975, Yin, J., Hoffmann, J., Kaestle, S. M., Neye, N., Wang, L., Baeurle, J., et al. In March 2020, the World Health Organization (WHO) declared Coronavirus Disease 2019 (COVID-19) a pandemic, therefore the efforts of scientists around the world are focused on finding the right treatment and vaccine for the novel disease. Bethesda, MD 20894, Web Policies (2020). Pharmacol. 108 (6), 11851194. TABLE 3. 291 (6), L1207L1219. Before Transient Receptor Potential Vanilloid 4-Mediated Disruption of the Alveolar Septal Barrier. doi:10.1073/pnas.160041997, Leroy, C., Priv, A., Bourret, J.-C., Berthiaume, Y., Ferraro, P., and Brochiero, E. (2006). doi:10.1093/ofid/ofaa105/5811022, Minakata, Y., Suzuki, S., Grygorczyk, C., Dagenais, A., and Berthiaume, Y. Cepharanthine: a Review of the Antiviral Potential of a Japanese-approved Alopecia Drug in COVID-19. 1 (4), 100052. doi:10.1016/j.xcrm.2020.100052, Shen, C., Wang, Z., Zhao, F., Yang, Y., Li, J., Yuan, J., et al. Decreased expression of alveolar Na-K-ATPase, dysregulation of sodium and potassium channels, aquaporins, and renin angiotensin system, and abnormal metabolism of bradykinin and hyaluronic acid as well as cytokine inflammatory storm all lead to ARDS and pulmonary edema. HA-related hydrogel has been found in both, ARDS and SARS. Cell 181 (2), 281292. In addition, potassium channels can act as oxygen sensors in alveolar epithelium and thus adjust lung function to environmental changes in O2 levels (Bartoszewski et al., 2017).

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