Intensive Care Med. Clin. 11, 1708. doi:10.3389/fimmu.2020.01708, Thanh Le, T., Andreadakis, Z., Kumar, A., Gmez Romn, R., Tollefsen, S., Saville, M., et al. 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). J. Endocrinol. PCTR1 Improves Pulmonary Edema Fluid Clearance through Activating the Sodium Channel and Lymphatic Drainage in Lipopolysaccharideinduced ARDS. 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. COVID19 Diagnosis and Management: a Comprehensive Review. 274, L203L211. 318 (4), L723L741. medRxiv.doi:10.1101/2020.05.20.20107607, Hu, K., Guan, W.-j., Bi, Y., Zhang, W., Li, L., Zhang, B., et al. The Serum and Glucocorticoid Kinase Sgk Increases the Abundance of Epithelial Sodium Channels in the Plasma Membrane of Xenopus Oocytes. (2014). doi:10.1101/2020.03.20.20039586, Londino, J. D., Lazrak, A., Collawn, J. F., Bebok, Z., Harrod, K. S., and Matalon, S. (2017). 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. Epithelial sodium channel (ENaC), present in human lungs, kidneys and other organs, plays a vital role in lung fluid clearance (Figure 4 Mechanism of inhibiting ENaC inducing pulmonary edema) (Matthay et al., 2002). He had no cough, expectoration, nasal discharge or sore throat. Diagnosing COVID-19: The Disease and Tools for Detection. 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. Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. doi:10.1111/joim.13091, Passi, A., Negrini, D., Albertini, R., de Luca, G., and Miserocchi, G. (1998). Association between Early Treatment with Qingfei Paidu Decoction and Favorable Clinical Outcomes in Patients with COVID-19: A Retrospective Multicenter Cohort Study. J. Physiology-Lung Cell Mol. In the meantime, we urgently need potent reduction in fatality of COVID-19. Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. (2020b). doi:10.1161/01.cir.37.1.45, Cai, J., Li, H., Zhang, C., Chen, Z., Liu, H., Lei, F., et al. FIGURE 5. J. Pharmacol. Mil. 2021 May 7;8:644678. doi: 10.3389/fmed.2021.644678. (2020c). 2023 Feb 14;14:1080962. doi: 10.3389/fphar.2023.1080962. K+ Channels Regulate ENaC Expression via Changes in Promoter Activity and Control Fluid Clearance in Alveolar Epithelial Cells. Annu. Not everyone gets side effects. 74 (2), 92101. Patients in intensive care units (ICU) have higher plasma levels of IL2, IL7, IL10, MCP1, MIP1A, GSCF, IP10, and TNF (Huang et al., 2020). Immune responses to COVID-19 vaccinations may trigger acute exacerbations in idiopathic pulmonary fibrosis among susceptible patients, according to data published in the American Journal of. doi:10.1074/jbc.M100322200, Udugama, B., Kadhiresan, P., Kozlowski, H. N., Malekjahani, A., Osborne, M., Li, V. Y. C., et al. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. Am. K+ Channel Openers Restore Verapamil-Inhibited Lung Fluid Resolution and Transepithelial Ion Transport. doi:10.1016/s0140-6736(20)30183-5, Hui, D. S. C., and Zumla, A. Ion Channels of the Lung and Their Role in Disease Pathogenesis. 39 (270), H2000H2007. J. Biol. Repurposed drugs with proofs of antiviral effects for other viral infections have been tried. J. Biol. Rev. Qu, G. J. N. Engl. includes glycoproteins, membranes and nucleic acids. BMJ 369, m1432. doi:10.1001/jama.2020.10044, Lippi, G., South, A. M., and Henry, B. M. (2020). Invest. J. Exuberant Elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 Infection Is Associated with Disease Severity and Fatal Outcome. He was medicated with methylprednisolone 1 mg/kg and diuretics and recovered rapidly. The Origin, Transmission and Clinical Therapies on Coronavirus Disease 2019 (COVID-19) Outbreak - an Update on the Status. The fluid transudes into and accumulates in the interstitium of lungs and finally alveolars from lung capillary, leading to severe disorder of pulmonary ventilation and gas exchange (Staub, 1974). So far, only remdesivir was approved by FDA for the compassionate use in severe infected COVID-19 patients (Beigel et al., 2020). Potential drugs for normalizing humoral metabolism. doi:10.1007/s00018-007-6228-6, Itani, O. Am. Accessibility getting a COVID-19 vaccine is one way to lower the chance of developing . TRPs are essential for the respiratory system and pulmonary edema, in which TRPA1, TRPV1 and TRPV4 are the most important. medRxiv. Lung Cel Mol Physiol 282, L631L641. COVID-19 Infection: the Perspectives on Immune Responses. doi:10.1161/CIRCRESAHA.107.168724, Yin, J., Michalick, L., Tang, C., Tabuchi, A., Goldenberg, N., Dan, Q., et al. Res. 225 (4), 618627. 388 (4), 421436. Pharmacol. Cell 181 (2), 281292. 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). FIGURE 6. eCollection 2021. BK is generated by cleavage of high-molecular-weight kininogen (HMWK) from plasma-kallikrein and binds to the BKB2 receptor, and thus results vascular hemorrhage (Garvin et al., 2020). 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. 2020. J. Cel Physiol 234 (11), 2005720065. 2021 Jan;93(1):94-96. doi: 10.1002/jmv.26152. Convalescent plasma have been initially shown to be beneficial for COVID-19 patients with severe infection stabilizing the immune system (Shen et al., 2020), but the subsequent randomized controlled trial did not show significant improvement within 28days (Li et al., 2020). (1999). An official website of the United States government. J. Respir. [Effect of Astragali Radix in Improving Early Renal Damage in Metabolic Syndrome Rats through ACE2/Mas Pathway]. Lung Injury in COVID-19 Has Pulmonary Edema as an Important Component and Treatment with Furosemide and Negative Fluid Balance (NEGBAL) Decreases Mortality. Med. J. Physiology-Lung Cell Mol. Care 21 (1), 305. doi:10.1186/s13054-017-1882-z, Zhang, H., Kang, Z., Gong, H., Xu, D., Wang, J., Li, Z., et al. Eur. 274 (53), 3783437839. Circuits between Infected Macrophages and T Cells in SARS-CoV-2 Pneumonia. Epub 2020 May 13. J. Physiology-Lung Cell Mol. doi:10.5582/ddt.2020.03070, Ahmed, M. H., and Hassan, A. SODIUM CHANNELS IN ALVEOLAR EPITHELIAL CELLS: Molecular Characterization, Biophysical Properties, and Physiological Significance. 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). Glucocorticoids were shown to have the ability of inducing de novo synthesis of ENaC (Chow et al., 1999; Otulakowski et al., 1999; Sayegh et al., 1999) and affecting ENaC regulatory pathway via serum and glucocorticoids-inducible kinase-1 (SGK-1) (Chen et al., 1999; de la Rosa et al., 1999; Itani et al., 2001; Zhang et al., 2007). ACS Nano 14 (4), 38223835. Rhinovirus Upregulates Transient Receptor Potential Channels in a Human Neuronal Cell Line: Implications for Respiratory Virus-Induced Cough Reflex Sensitivity. CD44 inhibition reduces the IL-2 induced vascular leakage syndrome, revealing that CD44 may act as a potential target in COVID-19 treatment. doi:10.1016/s2213-2600(20)30076-x, Yan, H., Valdes, A. M., Vijay, A., Wang, S., Liang, L., Yang, S., et al. Anti-hypertensive Angiotensin II Receptor Blockers Associated to Mitigation of Disease Severity in Elderly COVID-19 Patients. Epub 2020 Jun 20. (1999). 2021 Jun 7;12:664349. doi: 10.3389/fphar.2021.664349. (2017). In these patients, white blood cells count, neutrophil count and D-dimer level keep rising while lymphocyte count keeps decreasing as the disease progresses. Aldosterone-induced Sgk1 Relieves Dot1a-Af9-Mediated Transcriptional Repression of Epithelial Na+ Channel . J. Clin. Epub 2020 Jun 29. The abnormal humoral metabolism in lungs and the resulting pulmonary edema have become the main life-threatening factors in COVID-19 patients. 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. 46 (2), 208214. 1480 (1), 73103. (2020). Moreover, as a retrospective multicenter cohort study reported, early treatment with Qing-Fei-Pai-Du Decoction associated with better outcomes, faster recovery, and a shorter duration of hospital stay (Shi et al., 2020a). 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. 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. Immunol. 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). 8 (5), 475481. (2009). Cel Metab. Am. Ursodeoxycholic Acid Stimulates Alveolar Fluid Clearance in LPSinduced Pulmonary Edema via ALX/cAMP/PI3K Pathway. Recombinant ACE2 was also reported to be a potential therapy in the clinical study of ARDS, which can lead to rapid decrease of plasma Ang II level and IL-6 expression. Thus, it could be a potential RdRp inhibitor for SARS-CoV-2 (Lung et al., 2020). doi:10.1161/01.RES.0000247065.11756.19, Andr, E., Gatti, R., Trevisani, M., Preti, D., Baraldi, P., Patacchini, R., et al. Polymodal Transient Receptor Potential Vanilloid Type 1 Nocisensor. Natl. 64 (15), 20062012. Endocrinology in the Time of COVID-19: Management of Diabetes Insipidus and Hyponatraemia. Acad. Ion channels, AQPs, RAS, bradykinin and hyaluronic acid are factors influencing the pulmonary edema. The University of Connecticut Foundation, Inc. Office of Development and Alumni Relations 10 Talcott Notch Road Suite 100 Farmington, CT 06032 TALLAHASSEE, Fla. Florida Surgeon General Joseph Ladapo personally altered a state-driven study about Covid-19 vaccines last year to suggest that some doses pose a . TRPA1 Agonists Evoke Coughing in guinea Pig and Human Volunteers. 158 (6), 16211628. doi:10.1007/s11596-015-1490-6, Jovanovi, S., Crawford, R. M., Ranki, H. J., and Jovanovi, A. 1 (4), 100052. doi:10.1016/j.xcrm.2020.100052, Shen, C., Wang, Z., Zhao, F., Yang, Y., Li, J., Yuan, J., et al. [Med. Efficacy and Safety of Lianhuaqingwen Capsules, a Repurposed Chinese Herb, in Patients with Coronavirus Disease 2019: A Multicenter, Prospective, Randomized Controlled Trial. Lianhuaqingwen Exerts Anti-viral and Anti-inflammatory Activity against Novel Coronavirus (SARS-CoV-2). Mol. Epub 2022 Oct 17. Available: http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml (Accessed February 4, 2021). Currently, these symptoms are the primary consequences of pulmonary virus infection. medRxiv. (2020d). Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective. Semin. Am. 289 (1), L104L110. Proteoglycan Involvement during Development of Lesional Pulmonary Edema. In early April 2021, an 86-year-old man presented to the emergency department with a 1-day history of weakness, dyspnoea and fever. Clin. The general regulation approaches of AFC. China Life Sci. Among the currently pursued therapeutic strategies against COVID-19, little attention has been paid to abnormal lung humoral metabolism. Symptoms that are common to all of these conditions include cough and shortness of breath. 61, 35. doi:10.1146/annurev.physiol.61.1.627, Matthay, M. A., Clerici, C., and Saumon, G. (2002). Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human ACE2. 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). As Towne et al., (2001) reported, AQP-5 expression significantly declined during pulmonary inflammation and edema, and TNF- decreased AQP5 mRNA and protein expression levels via TNFR1 and NF-B pathway (Towne et al., 2001). Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. Infection and replication process of SARS-CoV-2. Pharmacol. 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). (2020). Res. Chem. doi:10.7554/eLife.59177, George, P. M., Wells, A. U., and Jenkins, R. G. (2020). Sodium transport is the main ion transport involved in the AFC. Coronavirus; Race and Medicine . The structure of coronavirus (Figure 1 A vision of coronavirus with the minimal set of structural proteins.) Decreased Expression of Both the 1- and 2-subunits of the Na-K-ATPase Reduces Maximal Alveolar Epithelial Fluid Clearance. doi:10.1073/pnas.1216382110, Staub, N. C. (1974). Med. Diagn Pathol. Med. medRxiv. Amiloride, a prototypic inhibitor of ENaC, might also have a potential in treating COVID-19 patients. Care Med. Dexamethasone for the Treatment of Coronavirus Disease (COVID-19): a Review. Calcium Antagonists and Their Mode of Action: an Historical Overview. Res. Abnormal humoral metabolism is mainly manifested as imbalances of water and electrolytes. 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). J. Physiology-Lung Cell Mol. Pulmonary vessels and perfusion are frequently abnormal in coronavirus disease 2019 (COVID-19) pneumonia and may point to a key role of pulmonary vascular pathology and hypoxemia in COVID-19. COVID-19 can cause lung complications such as pneumonia and, in the most severe cases, acute respiratory distress syndrome, or ARDS . annals 99 (1), 1216. Chloroquine and Hydroxychloroquine in Covid-19. COVID-19 and its Implications for Thrombosis and Anticoagulation. Response of Thiazide-Induced Hypokalemia to Amiloride. 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). 1, 2 More recently, six cases of. Invited Review: Active Fluid Clearance from the Distal Air Spaces of the Lung. HA-related hydrogel has been found in both, ARDS and SARS. COVID-19 patients often have pathological features such as pulmonary interstitial or alveolar edema, diffuse tracheal phlegm thrombus and pulmonary inflammatory lymphoid infiltration, and are prone to acute respiratory distress syndrome (ARDS), causing lung injury (Cutts et al., 2017). Dexmedetomidine can upregulate AQP-1 and AQP-5 expression in rats with acute lung injury induced by LPS and thus induce pulmonary edema (Jiang et al., 2015).
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