Glucocorticoid-stimulated Lung Epithelial Na(+) Transport Is Associated with Regulated ENaC and Sgk1 Expression. Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective. (2020). JAMA 323 (16), 15821589. J. Respir. -. It was observed that the expression of ENaC and Na+/K+-ATPase in primary alveolar type II cells from rat lungs increased responding to terbutaline (Minakata et al., 1998). Am. doi:10.1007/s11596-015-1490-6, Jovanovi, S., Crawford, R. M., Ranki, H. J., and Jovanovi, A. J. Intern. doi:10.1161/01.RES.0000247065.11756.19, Andr, E., Gatti, R., Trevisani, M., Preti, D., Baraldi, P., Patacchini, R., et al. Physiol. Accessibility Also, thrombocytopenia and thrombosis have been mostly reported after AstraZeneca (ChAdOx1 nCoV-19) and Johnson & Johnson/Janssen COVID-19 vaccines [ 3 ]. 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). Clin. Qu, G. J. Natl. 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 TRP Ion Channel Family. Comment on "Organprotective Effect of Angiotensinconverting Enzyme 2 and its Effect on the Prognosis of COVID19". As such, TRPV4 inhibition likely has protective and beneficial effect on mucus clearance and pulmonary edema. These in turn, lead to severe lung damage in COVID-19 patients. TABLE 1. Am. doi:10.1182/blood.2020006000, Couto, M., de Diego, A., Perpii, M., Delgado, L., and Moreira, A. This may be due to lingering inflammation and other factors. Sci. CFTR inhibitors, like glibenclamide and CFTRinh-172 inhibitor, distinctly reduced absorptive alveolar fluid transport (Solymosi et al., 2013). 180 (11), 10421047. Immune-modulatory agents, supportive cares, and antiviral drugs have been tested as COVID-19 treatments in patients with severe infections (Pascarella et al., 2020; Ren et al., 2020). COVID-19 mortality is primarily driven by abnormal alveolar fluid metabolism of the lung, leading to fluid accumulation in the alveolar airspace. doi:10.5114/pdia.2013.37040, Cui, M., Gosu, V., Basith, S., Hong, S., and Choi, S. (2016). 171 (10), 24742507. Care Med. All authors contributed to manuscript revision, read, and approved the submitted version. (2008). 161, 105290. doi:10.1016/j.phrs.2020.105290, Shi, Y., Wang, Y., Shao, C., Huang, J., Gan, J., Huang, X., et al. Immunopharmacology and Immunotoxicology 36 (6), 420425. However, further researches into the mode of action, efficacy and safety of these drugs are required. doi:10.5582/ddt.2020.03070, Ahmed, M. H., and Hassan, A. 6, 331345. (2020). The integrity of PG molecules in the vascular capillary basement membrane can make sure that endothelial permeability to fluid and solutes in a low level. 308 (11), L1136L1144. Potentially, glucocorticoids can be used as anti-inflammatory drugs in ARDS and pulmonary edema as well as in COVID-19 patients. The activities of the molecules in RAS are ruled by dynamic changes responding to an injury. doi:10.1164/rccm.200905-0665OC, Bull, M. B., and Laragh, J. H. (1968). His lab findings and clinical course were consistent with those of MIS after COVID-19 vaccination. 2, 26372646. 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. Cell. Endocrinology in the Time of COVID-19: Management of Diabetes Insipidus and Hyponatraemia. Most side effects are mild and normally last only a day or two. Pharmacol. COVID-19: Urgent Reconsideration of Lung Edema as a Preventable Outcome: Inhibition of TRPV4 As a Promising and Feasible Approach. Original Article Antibody Responses to Haemophilus influenzae Type b Vaccines in Men with Human . Am J Physiol Lung Cell Mol Physiol. Consequently, drugs that can normalize humoral metabolism should be clinically evaluated for their use in the treatment of COVID-19 patients (Table 1). 158 (6), 16211628. Pharmacol. 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. Am. Physiology 23, 360370. J. Physiol. 23 (5), 289301. (2020). Among the currently pursued therapeutic strategies against COVID-19, little attention has been paid to abnormal lung humoral metabolism. Acta (Bba) - Gen. doi:10.1038/s41586-020-03148-w, Guan, W.-j., Ni, Z.-y., Hu, Y., Liang, W.-h., Ou, C.-q., He, J.-x., et al. Transient Receptor Potential (TRP) Channels: a Clinical Perspective. COVID-19 Treatment and Diagnosis Guideline (7th version, trial) [Online]. doi:10.1530/EJE-20-0338, Clapham, D. E., Runnels, L. W., and Strbing, C. (2001). Med. IFN will continually induce inflammatory cytokines released by alveolar macrophages, promoting the activation of T cells and forming a positive feedback loop that drives persistent alveolar inflammation (Grant et al., 2021). Immunol. Proc. Tumor Necrosis Factor- Inhibits Aquaporin 5 Expression in Mouse Lung Epithelial Cells. Immunol. Physiol. Structure and Hormone Responsiveness of the Gene Encoding the -Subunit of the Rat Amiloride-Sensitive Epithelial Sodium Channel. Elife 9, e59177. Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control. TRPA1 distributes on C-fibers throughout the respiratory system (De Logu et al., 2016). 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). J. Physiology-Lung Cell Mol. Adipose-derived Exosomes Protect the Pulmonary Endothelial Barrier in Ventilator-Induced Lung Injury by Inhibiting the TRPV4/Ca2+ Signaling Pathway. doi:10.1146/annurev-virology-110615-042301, Li, L., Zhang, W., Hu, Y., Tong, X., Zheng, S., Yang, J., et al. Decreased Expression of Aquaporin-5 in Bleomycin-Induced Lung Fibrosis in the Mouse fibrosis in the Mouse. Mol. Exp. "It is the macroscopic image of an old myocardial infarction and pulmonary edema under further laboratory investigation," medical examiner Nikos Kalogrias reportedly said on Wednesday. 2021 Jan;93(1):94-96. doi: 10.1002/jmv.26152. Am. -, Adil M. S., Narayanan S. P., Somanath P. R. (2020). PCTR1 Improves Pulmonary Edema Fluid Clearance through Activating the Sodium Channel and Lymphatic Drainage in Lipopolysaccharideinduced ARDS. N. Engl. Life Sci. 92 (9), 14231424. The Clinical Benefits of Chinese Patent Medicines against COVID-19 Based on Current Evidence. Prc, N. H. C. o. t. (2020). 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. 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). Toxin means various pathogenic microorganism and inflammatory storm presenting in infected patients, and dampness means the abnormal humoral metabolism like inflammatory exudation. Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on 2 -Adrenergic Receptor Signaling. Am. Physiol. 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. Papi A, Stapleton RD, Shore PM, Bica MA, Chen Y, Larbig M, Welte T. Lung. doi:10.1203/00006450-199908000-00014, Christ-Crain, M., Hoorn, E. J., Sherlock, M., Thompson, C. J., and Wass, J. Other anti-viral drugs, such as arbidol, chloroquine phosphate and ritonavir, did not exhibit efficacy in randomized, placebo-controlled trials in COVID-19 patients. Res. The structure of coronavirus (Figure 1 A vision of coronavirus with the minimal set of structural proteins.) (2020). The Potential Chemical Structure of antiSARSCoV2 RNAdependent RNA Polymerase. 288, 198114. doi:10.1016/j.virusres.2020.198114, Krlicka, A. L., Kruczkowska, A., Krajewska, M., and Kusztal, M. A. J. Physiology-Lung Cell Mol. Abstract Background Severe cardiogenic pulmonary edema is a . Rev. DD&T 14 (5), 256258. 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. Currently, these symptoms are the primary consequences of pulmonary virus infection. 8 (5), 475481. Chloride Transport-Driven Alveolar Fluid Secretion Is a Major Contributor to Cardiogenic Lung Edema. Biophys. medRxiv. For patients recovering from COVID-19 who have persistent, progressive, or new respiratory symptoms, we obtain PFTs including spirometry, lung volumes, and diffusion capacity. KCa3.1 (1-EBIO) and KATP (minoxidil) channel openers can greatly recover AFC in mice intratracheally administrated verapamil, which is the first generation of the phenylalkylamine class of calcium channel antagonists (Fleckenstein, 1977; Nayler and Dillon, 1986), suggesting that K+ channel openers might be potential drugs for treating pulmonary edema (Han et al., 2010). Ijerph 17 (15), 5320. doi:10.3390/ijerph17155320, Kunzelmann, K., Beesley, A. H., King, N. J., Karupiah, G., Young, J. The spike (S) protein of coronavirus, one of the surface glycoproteins, is divided into two functional units, S1 and S2. (2020). [Effect of Astragali Radix in Improving Early Renal Damage in Metabolic Syndrome Rats through ACE2/Mas Pathway]. doi:10.1126/scitranslmed.3004276, Towne, J. E., Krane, C. M., Bachurski, C. J., and Menon, A. G. (2001). Careers. Nervous system conditions or surgeries. Lancet Respir. This buildup of fluid leads to shortness of breath. Chem. 99 (9), 988995. SN Compr. J. Ethnopharmacology 265, 113301. doi:10.1016/j.jep.2020.113301, Li, F. (2016). 2020 Aug 14;15(1):103. doi: 10.1186/s13000-020-01017-8. Clinical and Computed Tomographic Imaging Features of Novel Coronavirus Pneumonia Caused by SARS-CoV-2. TRPA1 Agonists Evoke Coughing in guinea Pig and Human Volunteers. EM did the language polishing. There are multiple potential mechanisms leading to pulmonary edema in severe Coronavirus Disease (COVID-19) patients and understanding of those mechanisms may enable proper management of this condition. Santos JLF, Zanardi P, Alo V, Dos Santos V, Bovone L, Rodriguez M, Magdaleno F, De Langhe V, Villoldo A, Martinez Souvielle R, Alconcher J, Quiros D, Milicchio C, Garcia Saiz E. J Clin Med. doi:10.1101/2020.04.24.2007787510.1002/cpt.2047, Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., and Zhou, Q. (2007). 274 (53), 3783437839. (2020b). Respir. (2006). Pharmacol. doi:10.1016/j.jaci.2020.08.038, Keywords: COVID-19, pulmonary edema, abnormal lung humoral metabolism, syndrome coronavirus 2, drug, traditional Chinese medicine, Citation: Cui X, Chen W, Zhou H, Gong Y, Zhu B, Lv X, Guo H, Duan J, Zhou J, Marcon E and Ma H (2021) Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential. doi:10.1016/s2213-2600(20)30225-3, Goldenberg, N. M., Ravindran, K., and Kuebler, W. M. (2015). Glucocorticoids, especially dexamethasone, have already been applied in the clinical treatment of COVID-19. -, Achanta S., Jordt S. E. (2020). Specific Pharmacology of Calcium in Myocardium, Cardiac Pacemakers, and Vascular Smooth Muscle. It is worth mentioning that, except alveoli, which is widely known as the target tissue, cardiomyocyte can be infected as well. (1999). Ann. 3 (1), 237261. Physiol. In these patients, white blood cells count, neutrophil count and D-dimer level keep rising while lymphocyte count keeps decreasing as the disease progresses. 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. Crit. doi:10.1002/jmv.25761, Luo, X., Ni, X., Lin, J., Zhang, Y., Wu, L., Huang, D., et al. 61, 35. doi:10.1146/annurev.physiol.61.1.627, Matthay, M. A., Clerici, C., and Saumon, G. (2002). Transient Receptor Potential Ankyrin Receptor 1 Is a Novel Target for Pro-tussive Agents. (2020). Zhou et al. 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). No use, distribution or reproduction is permitted which does not comply with these terms. 157, 104882. doi:10.1016/j.phrs.2020.104882, Zhang, H., and Baker, A. JAMA 323 (20), 20522059. Cmp 6 (1), 1327. J. Med. For instance, angiotensin II (Ang II) can typically generate vasoconstriction and sodium retention when binding to the AGTR1 receptor and vice versa via the AGTR2 receptor (Garvin et al., 2020). Aquaporins in the Lung. Pharmacol. doi:10.1038/d41573-020-00073-5, Thorneloe, K. S., Cheung, M., Bao, W., Alsaid, H., Lenhard, S., Jian, M.-Y., et al. 2022 Dec;134:102427. doi: 10.1016/j.artmed.2022.102427. doi:10.1101/2020.03.20.20039586, Londino, J. D., Lazrak, A., Collawn, J. F., Bebok, Z., Harrod, K. S., and Matalon, S. (2017). Amiloride. J. Med. Aldosterone-induced Sgk1 Relieves Dot1a-Af9-Mediated Transcriptional Repression of Epithelial Na+ Channel . J. Clin. Invest. Proteoglycan Involvement during Development of Lesional Pulmonary Edema. These cytokine storms can be treated with steroids, IL-1 antagonists, TNF inhibitors, and Janus kinase inhibitor (JAK) inhibitors (McCreary and Pogue, 2020). Currently, many clinical trials are in progress to test coronavirus treatment, including new drugs and drug repurposing or repositioning. 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. doi:10.2174/1874467211306010003, Gabazza, E. C., Kasper, M., Ohta, K., Keane, M., D'Alessandro-Gabazza, C., Fujimoto, H., et al. (1986). Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. JAMA 324 (5), 460470. Thus, the relieve of pulmonary edema should be one of the critical concerns in terms of the treatment of COVID-19 patients. Among all vaccine recipients, 66.6% reported at least one systemic reaction in the 7 days after vaccination. Res. Yes. After internal reviews of the reports, the CDC "did not find any data suggesting a link between Covid-19 vaccines and tinnitus," an agency . HHS Vulnerability Disclosure, Help Virol. We argue for expeditious clinical testing of this inhibitor in COVID-19 patients with respiratory malfunction and at risk for lung edema. (Imai et al., 2007; Zhang and Baker, 2017). Severe Acute Respiratory Syndrome. 2020. doi:10.1136/thoraxjnl-2013-203894, PubMed Abstract | CrossRef Full Text | Google Scholar, Achanta, S., and Jordt, S. E. (2020). (1985) 93 (4), 15331541. Researches proved that SARS-CoV-2 can directly infect human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as an engineered heart tissue (EHT), in cellular and organ level respectively, suggesting that the virus can replicate rapidly in the cardiomyocytes, infecting other cardiomyocytes, contributing to cardiomyocyte cell death, myocardial inflammation and even heart failure (Sharma et al., 2020; Bailey et al., 2021). He was medicated with methylprednisolone 1 mg/kg and diuretics and recovered rapidly. 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). Pharmacol. doi:10.1074/jbc.274.18.12431, Schlagenhauf, P., Grobusch, M. P., Maier, J. D., and Gautret, P. (2020). 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. doi:10.1002/jcp.29758, Zhang, W., Xia, X., Reisenauer, M. R., Rieg, T., Lang, F., Kuhl, D., et al. doi:10.1007/s00424-018-2232-y, Woods, P. S., Tazi, M. F., Chesarino, N. M., Amer, A. O., and Davis, I. C. (2015). The activation of -adrenergic receptor, especially 2 (Mutlu et al., 2004), was found to stimulate Na+ and fluid reabsorption. J. Respir. ACE2 is most abundantly expressed in human vascular endothelial cells as well as alveolar and intestinal epithelial cells. 92 (6), 693697. Further, ARDS is sometimes initially diagnosed as pneumonia or pulmonary edema (fluid in the lungs from heart disease). doi:10.1146/annurev.pa.17.040177.001053, Fronius, M. (2013). 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. 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).
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