Comment on "Organprotective Effect of Angiotensinconverting Enzyme 2 and its Effect on the Prognosis of COVID19". 94 (8), 10911100. 16 (10), 17081717. doi:10.1152/ajplung.00290.2014, Ji, G., Chen, R., and Zheng, J. We speculate that treatment of lung-edema will lead to a lower mortality in COVID-19 patients with severe infections. 19 (5), 305306. 2020 Aug 14;15(1):103. doi: 10.1186/s13000-020-01017-8. N. Engl. 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). (2020a). (2005). Polymodal Transient Receptor Potential Vanilloid Type 1 Nocisensor. (2014). Pharmacol. FIGURE 2. Clin. J. Respir. doi:10.1002/jmv.25848, Cutts, S., Talboys, R., Paspula, C., Prempeh, E., Fanous, R., and Ail, D. (2017). Potentially, glucocorticoids can be used as anti-inflammatory drugs in ARDS and pulmonary edema as well as in COVID-19 patients. Res. Rev. The activation of -adrenergic receptor, especially 2 (Mutlu et al., 2004), was found to stimulate Na+ and fluid reabsorption. 157, 104820. doi:10.1016/j.phrs.2020.104820, Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J. a., Liu, H., et al. 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). Care Med. Chansu Injection Improves the Respiratory Function of Severe COVID-19 Patients. (2014). Dis. In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Pathological Findings of COVID-19 Associated with Acute Respiratory Distress Syndrome. These cytokine storms can be treated with steroids, IL-1 antagonists, TNF inhibitors, and Janus kinase inhibitor (JAK) inhibitors (McCreary and Pogue, 2020). 21, 97S107S. (2019). Res. J. Physiology-Lung Cell Mol. [Med. The site is secure. Potassium channels are usually involved in maintaining the reabsorption of Na+ and the steady state of electrochemical gradient, ions and body fluids in airway epithelial cells specifically. (2019). TRPV4, expressed in alveolar type I, type II cells and alveolar capillary endothelial cells, has been considered as a crucial regulator of alveolo-capillary barrier integrity (Alvarez et al., 2006; Yin et al., 2008; Goldenberg et al., 2015; Yin et al., 2016). A type of pulmonary edema called neurogenic pulmonary edema can occur after a head injury, seizure or brain . Acta (Bba) - Biomembranes 1818 (7), 16821690. doi:10.1111/jcmm.15146, Harada, H., and Takahashi, M. (2007). 155, 104743. doi:10.1016/j.phrs.2020.104743, Richardson, S., Hirsch, J. S., Narasimhan, M., Crawford, J. M., McGinn, T., Davidson, K. W., et al. Bookshelf As such, the S protein is essential for viral infection (Heald-Sargent and Gallagher, 2012; Li, 2016; Walls et al., 2020). Diagnosing COVID-19: The Disease and Tools for Detection. ), cell growth and death, as well as the degradation of damaged cells (Zhao et al., 2020). doi:10.1016/s1875-5364(18)30123-7, Zhang, D., Zhang, B., Lv, J.-T., Sa, R.-N., Zhang, X.-M., and Lin, Z.-J. Thus, it could be a potential RdRp inhibitor for SARS-CoV-2 (Lung et al., 2020). 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). Med. These in turn, lead to severe lung damage in COVID-19 patients. (2014). Artif Intell Med. Ion channels, AQPs, RAS, bradykinin and hyaluronic acid are factors influencing the pulmonary edema. It has been reported that infection with a respiratory-associated virus can significantly increase the expression and activity of TRPV1 (Abdullah et al., 2014). 117 (3), 773783. (2021). (1999). 103, 7888. Glucocorticoid-stimulated Lung Epithelial Na(+) Transport Is Associated with Regulated ENaC and Sgk1 Expression. doi:10.1073/pnas.1216382110, Staub, N. C. (1974). 180 (11), 10421047. medRxiv. Pulmonary Fibrosis and COVID-19: the Potential Role for Antifibrotic Therapy. doi: 10.1152/ajplung.00161.2020. Association between Early Treatment with Qingfei Paidu Decoction and Favorable Clinical Outcomes in Patients with COVID-19: A Retrospective Multicenter Cohort Study. These channels are important in maintaining the optimum volume and ion constitution of bronchial periciliary fluid and alveolar lining fluid layers, which are necessary in appropriate pathogens mucociliary clearance and optimum gas exchange, respectively (Londino et al., 2017). doi:10.1152/ajplung.00255.2019, Zhang, B.-M., Wang, Z.-B., Xin, P., Wang, Q.-H., Bu, H., and Kuang, H.-X. S1 facilitates virus infection by binding to host receptors, and S2 regulates the membranes fusion to enable viral RNA entering into host cells for further replication. - Eur. He was medicated with methylprednisolone 1 mg/kg and diuretics and recovered rapidly. Cel Metab. As Gabazza et al., (2004) reported, lung fibrosis is linked to decreased mRNA and protein expression of AQP-5 in the lung. Ann. Hyponatremia (low blood sodium concentration) as well as low concentrations of potassium and calcium in the blood serum are also associated with COVID-19 (Lippi et al., 2020). Semin. Large Conductance Ca2+-Activated K+ Channels Sense Acute Changes in Oxygen Tension in Alveolar Epithelial Cells. doi:10.1152/ajplung.00464.2004, Lung, J., Lin, Y. S., Yang, Y. H., Chou, Y. L., Shu, L. H., Cheng, Y. C., et al. Virol. A pulmonary edema was the cause of the death of a woman who died short after a vaccine on Tuesday an autopsy has shown. COVID-19 mortality is primarily driven by abnormal alveolar fluid metabolism of the lung, leading to fluid accumulation in the alveolar airspace. 46 (2), 208214. doi:10.1002/jcp.29758, Zhang, W., Xia, X., Reisenauer, M. R., Rieg, T., Lang, F., Kuhl, D., et al. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Pharmacol. (2002). Please enable it to take advantage of the complete set of features! Front. It is worth mentioning that, except alveoli, which is widely known as the target tissue, cardiomyocyte can be infected as well. (2016). There are also several natural compounds which were previously shown to have positive effects on the lung edema-associated targets described in this paper (Zhou et al., 2006; Ho et al., 2007; Ji et al., 2014; Wang et al., 2015; Qu, 2019; Fan et al., 2020; Lung et al., 2020). J. Nat. Technol. Therefore, the excessive release and decreased hydrolysis of BK through activating BKB1 and BKB2 receptors result in extra vascular leakage and pulmonary edema (Figure 5 Mechanism of BK inducing pulmonary edema and potential drugs) (Zwaveling et al., 2020). 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). Intensive Care Med. Consequently, drugs that can normalize humoral metabolism should be clinically evaluated for their use in the treatment of COVID-19 patients (Table 1). SSRN. doi:10.1016/j.resp.2011.11.009, Fan, H.-H., Wang, L.-Q., Liu, W.-L., An, X.-P., Liu, Z.-D., He, X.-Q., et al. With treatment, most people with this type of pulmonary edema recover in about 24 hours. (2020a). 92 (6), 693697. Pharmacol. 10.1007/s42399-020-00610-8 Ready, Set, Fuse! Potential drugs for normalizing humoral metabolism. China Life Sci. Epithelial Sodium Channel Regulated by Aldosterone-Induced Protein Sgk. Care Med. Sepsis, another possible complication of COVID-19, can also cause lasting harm to the lungs and other organs. Improving the blood circulation can advance the oxygen supply for organs, accelerate the absorption of fluid and eventually improve pulmonary edema. However, among all current treatments mentioned above, little attention has been paid to the abnormal humoral metabolism and pulmonary edema, which is a key factor threatening patients lives. Thorax 69 (1), 4654. 388 (4), 421436. J. Respir. Impact of -adrenergic Agonist on Na+ Channel and Na+-K+-ATPase Expression in Alveolar Type II Cells. Who (2021). Sci. Proc. TGF--induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. Pharmaceuticals 13 (9), 259. doi:10.3390/ph13090259, Ren, J.-l., Zhang, A.-H., and Wang, X.-J. Subjects 1760 (1), 19. Am. doi:10.1002/jcp.28602, Otulakowski, G., Rafii, B., Bremner, H. R., and O'Brodovich, H. (1999). 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. 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. Anti-hypertensive Angiotensin II Receptor Blockers Associated to Mitigation of Disease Severity in Elderly COVID-19 Patients. doi:10.1152/ajplung.1998.275.2.L414, Mutlu, G. M., Dumasius, V., Burhop, J., McShane, P. J., Meng, F. J., Welch, L., et al. 64 (15), 20062012. Int. Nat. Protectin DX Increases Alveolar Fluid Clearance in Rats with Lipopolysaccharide-Induced Acute Lung Injury. As reported, PaO2/FiO2 and ROX index of patients receiving conventional treatment combined with toad venom injection (20ml/day) improved significantly (111.30 to 35.90 for PaO2/FiO2 and 7.56 to 2.94 for ROX). COVID-19 vaccines can cause mild side effects after the first or second dose, including: Pain, redness or swelling where the shot was given Fever Fatigue Headache Muscle pain Chills Joint pain Nausea and vomiting Swollen lymph nodes Feeling unwell Most side effects go away in a few days. Here, we describe molecular mechanisms of PFC and propose that proteins functioning in this process might serve as an underappreciated, but yet promising targets for reducing lung edema in severe COVID-19 patients. The latest research revealed that alveolar macrophages, which normally play a protective role, may also be infected by SARS-CoV-2 and release T cell chemokines, resulting large amounts of T cells gathering in lung and generating IFN. Am J Physiol Lung Cell Mol Physiol. Lung Cel Mol Physiol 282, L631L641. 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. People with pneumonia, lung cancer, or heart disease may experience chest pain or wheezing. (2010). Influenza Induces IL-8 and GM-CSF Secretion by Human Alveolar Epithelial Cells through HGF/c-Met and TGF-/EGFR Signaling. Thromb. (2020a). As reported, large-conductance calcium-activated potassium channels (BKCa) in alveoli can reduce alveoli opening during hypoxia, detect O2 variation, and adjust ion transport and fluid clearance (Jovanovi et al., 2003). Creative Commons Attribution License (CC BY). Open Forum Infect. 35 (19), 30142017. Mechanism of BK inducing pulmonary edema and potential drugs. RAS, especially several cleavage products of the peptide angiotensin (AGT) along with their receptors, maintains a balance of fluid volume and pressure. Amiloride was shown to induce the reduction of ACE2 expression in bronchial and alveolar epithelial cells (Adil et al., 2020) and can counteract the low cytosolic pH which has been observed in COVID-19 patients by acting on Na+/H+ exchanger (Cure and Cumhur Cure, 2020). J.I. Am J Physiol Lung Cell Mol Physiol. 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). Physiol. Traditional Chinese Medicine for COVID-19 Treatment. Pharmacol. medRxiv.doi:10.1101/2020.05.20.20107607, Hu, K., Guan, W.-j., Bi, Y., Zhang, W., Li, L., Zhang, B., et al. Adipose-derived Exosomes Protect the Pulmonary Endothelial Barrier in Ventilator-Induced Lung Injury by Inhibiting the TRPV4/Ca2+ Signaling Pathway. A recent review suggested that low-to-moderate doses of dexamethasone may lower the mortality rate in patients with severe infections (Ahmed and Hassan, 2020) and the latest finding indicated that the neutrophil-to-lymphocyte ratio determines the clinical efficacy of corticosteroid therapy in COVID-19 patients, as a neutrophil-to-lymphocyte ratio >6.11 associating with lower mortality in patients on corticosteroids (Cai et al., 2021). Most side effects are mild and normally last only a day or two. Biophys. doi:10.4049/jimmunol.1302421. doi:10.1074/jbc.M608358200, Harmer, D., Gilbert, M., and Borman, R. (2002). Chin. (2020). J. Med. 2020 Mar 23:3558887. doi: 10.2139/ssrn.3558887. (2020). CD44-dependent Intracellular and Extracellular Catabolism of Hyaluronic Acid by Hyaluronidase-1 and -2. 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. It shows the vaccine is teaching your body's immune system how to protect itself from the disease. Negative-feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-dependent Regulation of Transient Receptor Potential Vanilloid 4. J. Role of Drugs Used for Chronic Disease Management on Susceptibility and Severity of COVID19: A Large CaseControl Study. 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. J. Pharmacol. Mol. Inhibiting these TRPs may benefit the treatment of pulmonary edema. 173 (3), 281287. Zhongguo Zhong Yao Za Zhi 40 (21), 42454250. Respir. 275 (2), L414L422. 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). The University of Connecticut Foundation, Inc. Office of Development and Alumni Relations 10 Talcott Notch Road Suite 100 Farmington, CT 06032 Physiol. doi:10.1152/ajplung.00078.2015, Wsten-van Asperen, R. M., Lutter, R., Specht, P. A., Moll, G. N., van Woensel, J. 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 Neutrophil-To-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19. Idiopathic pulmonary fibrosis is also a risk factor for severe COVID-19 which can be observed in the CT scans of COVID-19 patients (Xu et al., 2020; George et al., 2020). (2020). doi:10.5114/pdia.2013.37040, Cui, M., Gosu, V., Basith, S., Hong, S., and Choi, S. (2016). An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure. COVID-19 Treatment and Diagnosis Guideline (7th version, trial) [Online]. (Engl) 133 (9), 10511056. Decreased Expression of Aquaporin-5 in Bleomycin-Induced Lung Fibrosis in the Mouse fibrosis in the Mouse. (1977). doi:10.1016/j.bbagen.2005.09.009, Zhuo, X.-J., Hao, Y., Cao, F., Yan, S.-F., Li, H., Wang, Q., et al. doi:10.5582/ddt.2020.03070, Ahmed, M. H., and Hassan, A. However, so far, no effective inhibitors have been developed against HAS2. Theaflavin from black tea was found to present a lower binding energy when it docks in the catalytic pocket of SARS-CoV-2 RdRp. Semin. In December 2019, a novel coronavirus, SARS-CoV-2, appeared, causing a wide range of symptoms, mainly respiratory infection. Chem. Life Sci. doi:10.1164/rccm.200905-0665OC, Bull, M. B., and Laragh, J. H. (1968). 289 (1), L104L110. The spike (S) protein of coronavirus, one of the surface glycoproteins, is divided into two functional units, S1 and S2. (2000). doi:10.1007/s11596-015-1490-6, Jovanovi, S., Crawford, R. M., Ranki, H. J., and Jovanovi, A. doi:10.1016/bs.apcsb.2015.11.005, Cure, E., and Cumhur Cure, M. (2020). COVID-19 can cause blood clots, even months after diagnosis. J. Biol. 2023 Apr;201(2):159-170. doi: 10.1007/s00408-023-00615-9. Biol. doi:10.1152/ajplung.00285.2017, Beigel, J. H., Tomashek, K. M., Dodd, L. E., Mehta, A. K., Zingman, B. S., Kalil, A. C., et al. Am. doi:10.1016/j.idc.2019.07.001, Imai, Y., Kuba, K., and Penninger, J. M. (2007). 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. Besides chemical drugs and compounds we discussed above, natural compounds and TCMs also possess promising antiviral effects against SARS-CoV-2 and had notably contribution in curing COVID-19, especially in alleviating pulmonary edema and preventing the disease development from mild to severe. Physiol. Other anti-viral drugs, such as arbidol, chloroquine phosphate and ritonavir, did not exhibit efficacy in randomized, placebo-controlled trials in COVID-19 patients. getting a COVID-19 vaccine is one way to lower the chance of developing . Pulmonary Interstitial Pressure and Proteoglycans during Development of Pulmonary Edema. 183 (1), G9G15. Inhibiting the inflammatory storm can effectively alleviate pulmonary edema. First post-authorization U.S. doses of Janssen COVID -19 Vaccine. EM did the language polishing. However, the efficacy and safety of these drugs in COVID-19 patients are unclear. Unable to load your collection due to an error, Unable to load your delegates due to an error. J. Med. Cell. Immunol. Dis. Science 367 (6483), 12601263. 80 (4), 394400. In these patients, white blood cells count, neutrophil count and D-dimer level keep rising while lymphocyte count keeps decreasing as the disease progresses. Pharmacol. JAMA 323 (11), 10611069. doi:10.1038/s12276-018-0075-4, Zwaveling, S., Gerth van Wijk, R., and Karim, F. (2020).
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