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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). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. The Pfizer study defined their primary endpoint as cases of symptomatic, confirmed COVID-19 occurring at least seven days after the second injection, while Moderna counted symptomatic, confirmed COVID-19 cases occurring at least 14 days after the second injection. ACE2 is most abundantly expressed in human vascular endothelial cells as well as alveolar and intestinal epithelial cells. Creative Commons Attribution License (CC BY). A vision of coronavirus with the minimal set of structural proteins. doi:10.1152/ajpheart.1996.270.6.h2000, Negrini, D., Passi, A., and Moriondo, A. Semin. The https:// ensures that you are connecting to the medRxiv. Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. As such, TRPV4 inhibition likely has protective and beneficial effect on mucus clearance and pulmonary edema. doi:10.1002/jmv.25848, Cutts, S., Talboys, R., Paspula, C., Prempeh, E., Fanous, R., and Ail, D. (2017). 117 (3), 773783. Nat. Acad. (2000). Since the inhibition of ENaC induces pulmonary edema formation, targeting ENaC is rational in order to enhance fluid clearance from the alveoli. Most of the published data about this association come from case reports and series. SSRN. doi:10.1001/jama.249.2.237, Matalon, S. (1999). Transient Receptor Potential Channels in Pulmonary Chemical Injuries and as Countermeasure Targets. 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"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. doi:10.1161/01.cir.37.1.45, Cai, J., Li, H., Zhang, C., Chen, Z., Liu, H., Lei, F., 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). 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). It has been shown that the incidence and severity of COVID-19 are closely related to abnormal metabolism of inorganic salts. (2010). 63 (3), 457460. J. Biol. (2020). 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Influenza Induces IL-8 and GM-CSF Secretion by Human Alveolar Epithelial Cells through HGF/c-Met and TGF-/EGFR Signaling. Dis. Med Res 7 (1), 11. doi:10.1186/s40779-020-00240-0, Han, D.-Y., Nie, H.-G., Gu, X., Nayak, R. C., Su, X.-F., Fu, J., et al. 313 (5), L845L858. 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). Epub 2020 Jun 20. Efficacy and Safety of Lianhuaqingwen Capsules, a Repurposed Chinese Herb, in Patients with Coronavirus Disease 2019: A Multicenter, Prospective, Randomized Controlled Trial. J. Med. All authors contributed to manuscript revision, read, and approved the submitted version. doi:10.1016/j.bbagen.2005.09.009, Zhuo, X.-J., Hao, Y., Cao, F., Yan, S.-F., Li, H., Wang, Q., et al. Sci. doi:10.1097/CM9.0000000000000797, Ferner, R. E., and Aronson, J. K. (2020). A., et al. 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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). 19 (5), 305306. (1977). (2020). 8600 Rockville Pike Hormonal Regulation and Genomic Organization of the Human Amiloride-Sensitive Epithelial Sodium Channel Subunit Gene. Am. CFTR inhibitors, like glibenclamide and CFTRinh-172 inhibitor, distinctly reduced absorptive alveolar fluid transport (Solymosi et al., 2013). ), cell growth and death, as well as the degradation of damaged cells (Zhao et al., 2020). (2021). doi:10.1126/science.abb2507, Xu, X., Chen, P., Wang, J., Feng, J., Zhou, H., Li, X., et al. Immunol. HM designed the framework of the review. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. 4 (159), 159ra148. Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma. Cel Mol Biol 20 (5), 10281040. Abdullah H., Heaney L. G., Cosby S. L., McGarvey L. P. A. Clin. -. doi:10.1111/j.1476-5381.2009.00438.x, Bailey, A. L., Dmytrenko, O., Greenberg, L., Bredemeyer, A. L., Ma, P., Liu, J., et al. (2021). 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. (2020b). doi:10.1152/ajplung.1998.275.3.L631, Perkins, G. D., McAuley, D. F., Thickett, D. R., and Gao, F. (2006). 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. SARS-CoV-2 is an enveloped RNA coronavirus of the genus , and is the seventh coronavirus which can infect human (Xu et al., 2020). 92 (9), 14231424. 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%). Notably, both vaccines have strong safety profiles, with the most common adverse events including injection site reactions, fever, chills, fatigue, headache, and muscle and joint aches. 2021 May 7;8:644678. doi: 10.3389/fmed.2021.644678. Shapiro, S. D. (2001). J. Physiology-Lung Cell Mol. 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). Struct. J. Med. Ready, Set, Fuse! Before Some of these TCMs along with their constituent and antiviral and reducing pulmonary edema mechanisms are shown in Table 3. Chills and swollen lymph nodes can also occur. Received: 05 February 2021; Accepted: 25 May 2021;Published: 07 June 2021. In this review, we discuss the clinical characteristics of COVID-19, current as well as potential new treatments based on the reduction of lung edema through various means, drugs, TCMs or natural compounds. -, Achanta S., Jordt S. E. (2020). His lab findings and clinical course were consistent with those of MIS after COVID-19 vaccination. COVID-19, an infectious disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a global reach. Impaired Breakdown of Bradykinin and its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection. Regulation of ENaC and CFTR Expression with K+ Channel Modulators and Effect on Fluid Absorption across Alveolar Epithelial Cells. Anti-hypertensive Angiotensin II Receptor Blockers Associated to Mitigation of Disease Severity in Elderly COVID-19 Patients. However, the efficacy and safety of these drugs in COVID-19 patients are unclear. 7 (4). Moreover, it has been revealed that exosomes derived from human adipocyte can inhibit TRPV4-mediated calcium influx and thus protect mice against ventilator-induced lung injury (Yu et al., 2020). 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). Not everyone gets side effects. 97 (5), 543554. doi:10.1152/ajplung.00395.2015, Birrell, M. A., Belvisi, M. G., Grace, M., Sadofsky, L., Faruqi, S., Hele, D. J., et al. 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). As in lipopolysaccharide-induced acute lung injury, docosahexaenoic acid and its derivatives stimulate AFC through alveolar ENaC, Na,K-ATPase via ALX/cAMP/PI3K pathway (Wang et al., 2014; Zhang et al., 2017). 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). Cel Metab. doi:10.1007/s42399-020-00610-8, Ai, J.-W., Zhang, H.-C., Xu, T., Wu, J., Zhu, M., Yu, Y.-Q., et al. J. Med. Respir. 92 (6), 693697. It has been shown that the incidence and severity of COVID-19 are closely related to abnormal metabolism of inorganic salts. doi:10.1007/s00424-018-2232-y, Woods, P. S., Tazi, M. F., Chesarino, N. M., Amer, A. O., and Davis, I. C. (2015). (2020). doi:10.1016/j.cmet.2021.01.002, Chen, S.-y., Bhargava, A., Mastroberardino, L., Meijer, O. C., Wang, J., Buse, P., et al. doi:10.1074/jbc.274.53.37834, De Logu, F., Patacchini, R., Fontana, G., and Geppetti, P. (2016). Infection of Mice with Influenza A/WSN/33 (H1N1) Virus Alters Alveolar Type II Cell Phenotype. Ther. medRxiv. JAMA 324 (8), 782793. Several cases of vaccine-induced thrombotic thrombocytopenia from a similar viral vector vaccine (Oxford-AstraZeneca [ChAdOx1 nCoV-19]) have been reported. doi:10.1016/j.cell.2020.02.058, Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., et al. During the infection of SARS-CoV-2, RAS, BK and hyaluronic acid (HA) are all involved in the regulation of AFC and the formation of pulmonary edema (Garvin et al., 2020). 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). Infect. COVID-DSNet: A novel deep convolutional neural network for detection of coronavirus (SARS-CoV-2) cases from CT and Chest X-Ray images. Moreover, the peripheral blood mononuclear lymphocyte of COVID-19 patients was also greatly improved, from 0.91 0.54 to 1.24 0.67 after being treated for a week, while there was no obvious change in control group (Hu et al., 2020). By March 31st of 2021, a total of 128.54 million cases of severe Coronavirus Disease (COVID-19) have been diagnosed globally, and a total of 2.81 million people have died from the disease (WHO, 2021). Am. K+ Channel Openers Restore Verapamil-Inhibited Lung Fluid Resolution and Transepithelial Ion Transport. J. Cel Physiol 235 (12), 95109523. Large Conductance Ca2+-Activated K+ Channels Sense Acute Changes in Oxygen Tension in Alveolar Epithelial Cells. doi:10.1055/s-0040-1712960, Deng, J., Wang, D.-x., Deng, W., Li, C.-y., Tong, J., and Ma, H. (2012). As Gabazza et al., (2004) reported, lung fibrosis is linked to decreased mRNA and protein expression of AQP-5 in the lung. Chloroquine and Hydroxychloroquine in Covid-19. The TRP Ion Channel Family. COVID-19 Infection: the Perspectives on Immune Responses. Circ. 4 The -Agonist Lung Injury Trial (Balti). 10.1111/nyas.14472 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). Thorax 69 (1), 4654. AQP-5 plays a significant role in pulmonary edema and decreased expression of AQP-5 has been observed during the disease process. Life Sci. Physiol. Existing drugs and inhibitors targeting the components of humoral metabolism may serve as potential treatments for COVID-19 and should be further investigated. Immunopathol 38 (3), 321329. Am. 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). SARS-CoV-2 invasion leads to alveolar and vascular epithelial cells damage impelling the formation of minimal thrombus, increasing pulmonary venous pressure and vascular permeability and leading to massive loss of tissue fluid. (2020c). Res. Currently, these symptoms are the primary consequences of pulmonary virus infection. doi:10.1182/blood.2020006000, Couto, M., de Diego, A., Perpii, M., Delgado, L., and Moreira, A. 11, 1708. doi:10.3389/fimmu.2020.01708, Thanh Le, T., Andreadakis, Z., Kumar, A., Gmez Romn, R., Tollefsen, S., Saville, M., 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. [Effect of Astragali Radix in Improving Early Renal Damage in Metabolic Syndrome Rats through ACE2/Mas Pathway]. Chin. Mol. Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control. Optimizing Diagnostic Strategy for Novel Coronavirus Pneumonia, a Multi-center Study in Eastern China. government site. - Eur. doi:10.1152/ajplung.00085.2001, Ito, Y., Correll, K., Zemans, R. L., Leslie, C. C., Murphy, R. C., and Mason, R. J. J. Respir. 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. medRxiv. Angiotensin-converting Enzyme 2 in Acute Respiratory Distress Syndrome. TRP Functions in the Broncho-Pulmonary System. J. Physiology-Lung Cell Mol. Accumulation of HA can directly induce ARDS and pulmonary edema. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-Threatening COVID-19. doi:10.1111/nyas.14472, Adil, M. S., Narayanan, S. P., and Somanath, P. R. (2020). 388 (4), 421436. 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). Dexamethasone for the Treatment of Coronavirus Disease (COVID-19): a Review. SODIUM CHANNELS IN ALVEOLAR EPITHELIAL CELLS: Molecular Characterization, Biophysical Properties, and Physiological Significance. 173 (3), 281287. Serum sodium shows a decrease trend in CODIV-19 development (Krolicka et al., 2020). Med. doi:10.1101/2020.03.02.20029975, Yin, J., Hoffmann, J., Kaestle, S. M., Neye, N., Wang, L., Baeurle, J., et al. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. (2020). Thromb. 383, 23332344. Biophys. Nervous system conditions or surgeries. Direct Vascular Effects of Furosemide in Humans. doi:10.1074/jbc.M608358200, Harmer, D., Gilbert, M., and Borman, R. (2002). Qing-Fei-Pai-Du Decoction, which is officially recommended for the treatment of COVID-19 patients as mentioned in the guideline issued by NHC (Trial 7th edition) (PRC, 2020), has an effective rate higher than 90% (2020) and can mediate the inflammatory storm induced by COVID-19 (Yang et al., 2020b), regulate the innate immune, cytokine activities (IL-17, NF-B, TNF etc. (2014). Therefore, severe infections, which are induced by influenza virus, target the distal lung epithelial cells, inhibit the ENaC via activating protein kinase C (Kunzelmann et al., 2000), and damage the pulmonary surfactant (Hofer et al., 2015; Ito et al., 2015; Woods et al., 2015). 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. 2, 1019. (2020a). Second, autopsy results showed no evidence of acute infection or cardiovascular disease in the internal organs. Res. Lancet Respir. Physiol. Rev. Crit. (Engl) 133 (9), 10511056. Among the currently pursued therapeutic strategies against COVID-19, little attention has been paid to abnormal lung humoral metabolism. 346, 16311636. medRxiv. Acute Respiratory Distress Syndrome Leads to Reduced Ratio of ACE/ACE2 Activities and Is Prevented by Angiotensin-(1-7) or an Angiotensin II Receptor Antagonist. J. Physiology-Lung Cell Mol. Recently, several companies came out with vaccines against COVID-19 which have been approved for use. 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. doi:10.7554/eLife.59177, George, P. M., Wells, A. U., and Jenkins, R. G. (2020). Med. Papi A, Stapleton RD, Shore PM, Bica MA, Chen Y, Larbig M, Welte T. Lung. We also obtain PFTs in recovering COVID-19 patients with severe pulmonary involvement or COVID-19-related ARDS, which applies to many patients who required hospitalization. Science 367 (6483), 12601263. However, as we discussed above, the inhibition of ENaC can also induce pulmonary edema and further studies are required to determine the potential use of ENaC inhibitors for COVID-19 treatment. 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). Care Med. (2011). Repurposed drugs with proofs of antiviral effects for other viral infections have been tried. 1, 2 More recently, six cases of. FIGURE 2. Infection, pulmonary edema, lung cancer, aspiration, and pulmonary hemorrhage are some of the diseases that can cause consolidation. (2020d). Since hypokalemia is a major issue in severe COVID-19 patients (Lippi et al., 2020), amiloride with its potassium-sparing diuretic activity (Bull and Laragh, 1968) can potentially be used to restore normal serum potassium concentrations (Maronde et al., 1983). Res. 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. 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). Nat. Science 367 (6485), 14441448. These in turn, lead to severe lung damage in COVID-19 patients. doi:10.1001/jama.2020.1585, Wang, Q. Y., Liang, W., Jiang, C., Li, N. Y., Xu, H., Yang, M. N., et al. Aldosterone-induced Sgk1 Relieves Dot1a-Af9-Mediated Transcriptional Repression of Epithelial Na+ Channel . J. Clin. The general regulation approaches of AFC. 57 (3), 262265. The abnormal humoral metabolism and pulmonary edema contribute to the severity of symptoms and fatality of COVID-19 patients. doi:10.1146/annurev.pa.17.040177.001053, Fronius, M. (2013). Please enable it to take advantage of the complete set of features! Pediatr. Physiol. 146 (6), 14541455. Physiol. Virol. Thus, PGs play a key role in the formation of pulmonary edema. Mol. TGF--induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. 1 (4), 100052. doi:10.1016/j.xcrm.2020.100052, Shen, C., Wang, Z., Zhao, F., Yang, Y., Li, J., Yuan, J., et al. J. Blood 135 (23), 20332040. Lancet Respir. doi:10.1038/labinvest.2016.150, Zhang, P. h., Han, J., Cao, F., Liu, Y. j., Tian, C., Wu, C. h., et al. In December 2019, a novel coronavirus, SARS-CoV-2, appeared, causing a wide range of symptoms, mainly respiratory infection. TABLE 3. However, palpable lymphadenopathy commonly involving the axilla as an immune response to vaccination may present a clinical diagnostic dilemma especially in persons with . Gut 69 (6), 10101018. . doi:10.1111/joim.13091, Passi, A., Negrini, D., Albertini, R., de Luca, G., and Miserocchi, G. (1998). Artif Intell Med. Like all medicines, the coronavirus (COVID-19) vaccines can cause side effects. TABLE 2. Exuberant Elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 Infection Is Associated with Disease Severity and Fatal Outcome. Physiol. (2020). We argue for expeditious clinical testing of this inhibitor in COVID-19 patients with respiratory malfunction and at risk for lung edema. 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). The most commonly reported symptoms of post- COVID-19 syndrome include: Fatigue Symptoms that get worse after physical or mental effort Fever Lung (respiratory) symptoms, including difficulty breathing or shortness of breath and cough Other possible symptoms include: 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). JAMA 323 (20), 20522059. Among the currently pursued therapeutic strategies against COVID-19, little attention has been paid to abnormal lung humoral metabolism. Neurobiol. N. Engl. He had no cough, expectoration, nasal discharge or sore throat. Effect and Mechanism of Astragaloside A on Acute Respiratory Failure in Rats. COVID-19 Treatment and Diagnosis Guideline (7th version, trial) [Online]. Transient Receptor Potential Vanilloid 4-Mediated Disruption of the Alveolar Septal Barrier. Improving the blood circulation can advance the oxygen supply for organs, accelerate the absorption of fluid and eventually improve pulmonary edema. FEBS Lett. It is also highly expressed in cardiomyocytes, epithelial cells of renal proximal convoluted tubule, urothelial cells, esophagus, and ileum (Harmer et al., 2002; Zhang et al., 2020), facilitating a quick invasion of the human body by SARS-COV-2 and causing complications. Efficacy and Safety of Garadacimab in Combination with Standard of Care Treatment in Patients with Severe COVID-19. Certain vaccine-preventable diseases can also increase swelling of your airways and lungs.
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