Pathol. Cepharanthine: a Review of the Antiviral Potential of a Japanese-approved Alopecia Drug in COVID-19. CD44 inhibition reduces the IL-2 induced vascular leakage syndrome, revealing that CD44 may act as a potential target in COVID-19 treatment. Abnormal humoral metabolism is mainly manifested as imbalances of water and electrolytes. Thus, promoting the degradation of HA may be significant in the recovery process. Respir. Inhalation or infusion of salbutamol, a 2-adrenergic agonist, reduced the incidences of pulmonary edema (Sartori et al., 2002) and was found to be beneficial in ARDS patients (Perkins et al., 2006). 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. National Library of Medicine Transient Receptor Potential Vanilloid 4-Mediated Disruption of the Alveolar Septal Barrier. Tumor Necrosis Factor- Inhibits Aquaporin 5 Expression in Mouse Lung Epithelial Cells. Pulmonary edema is the disequilibrium between formation and reflux of lung tissue fluid leading to the absorption of massive tissue fluid by lung lymph and vein failure. J. Physiology-Lung Cell Mol. The likelihood of hypertensive patients developing COVID-19, who were treated by ARBs, was reported to decrease by 76% (Yan et al., 2020). Circulation 37 (1), 4553. Allergy Clin. Ursodeoxycholic Acid Stimulates Alveolar Fluid Clearance in LPSinduced Pulmonary Edema via ALX/cAMP/PI3K Pathway. Decreased Expression of Aquaporin-5 in Bleomycin-Induced Lung Fibrosis in the Mouse fibrosis in the Mouse. 158, 104850. doi:10.1016/j.phrs.2020.104850, Ma, Q., Qiu, M., Zhou, H., Chen, J., Yang, X., Deng, Z., et al. He was medicated with methylprednisolone 1 mg/kg and diuretics and recovered rapidly. TGF--induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. Rev. 94 (8), 10911100. Reaffirms recommendation for Janssen COVID-19 Vaccine. 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In addition, natural compounds and TCMs which generally have multiple targets should also be investigated, both in terms of their efficacy and safety. (2021). Am. Protectin DX Increases Alveolar Fluid Clearance in Rats with Lipopolysaccharide-Induced Acute Lung Injury. One day before symptom onset, he had received a COVID-19 mRNA vaccine. Natl. Toxin means various pathogenic microorganism and inflammatory storm presenting in infected patients, and dampness means the abnormal humoral metabolism like inflammatory exudation. However, further researches into the mode of action, efficacy and safety of these drugs are required. Zhou et al. His lab findings and clinical course were consistent with those of MIS after COVID-19 vaccination. Phytomedicine 85, 153242. doi:10.1016/j.phymed.2020.153242, Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. TRPV4: Physiological Role and Therapeutic Potential in Respiratory Diseases. 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Resolvin D1 Stimulates Alveolar Fluid Clearance through Alveolar Epithelial Sodium Channel, Na,K-ATPase via ALX/cAMP/PI3K Pathway in Lipopolysaccharide-Induced Acute Lung Injury. COVID-19 mortality is primarily driven by abnormal alveolar fluid metabolism of the lung, leading to fluid accumulation in the alveolar airspace. 2023 Feb 13;11(2):435. doi: 10.3390/vaccines11020435. (2020a). Multiple TCMs have been already clinical applied for COVID-19 in China and achieved high recovery rate. (2020). The activities of the molecules in RAS are ruled by dynamic changes responding to an injury. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized with COVID-19 in the New York City Area. Nat. COVID-19, an infectious disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a global reach. Acad. 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. 46 (7), 835837. J. Physiology-Lung Cell Mol. Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. COVID-19 Vaccine: A Comprehensive Status Report. ACE2 is most abundantly expressed in human vascular endothelial cells as well as alveolar and intestinal epithelial cells. SN Compr. Pulmonary Edema in COVID19-A Neural Hypothesis - PubMed Pulmonary edema - Symptoms and causes - Mayo Clinic Potassium channels modulate the expression of ENaC. Chloride Transport-Driven Alveolar Fluid Secretion Is a Major Contributor to Cardiogenic Lung Edema. SARS-CoV-2 may act in a similar way. Physiol. (2020). 157, 104820. doi:10.1016/j.phrs.2020.104820, Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J. a., Liu, H., et al. Treatment of Pulmonary Edema by ENaC Activators/Stimulators. Liu Shen Capsule Shows Antiviral and Anti-inflammatory Abilities against Novel Coronavirus SARS-CoV-2 via Suppression of NF-b Signaling Pathway. Pulmonary Fibrosis and COVID-19: the Potential Role for Antifibrotic Therapy. 275 (2), L414L422. 2021 Jan;93(1):94-96. doi: 10.1002/jmv.26152. This may be due to lingering inflammation and other factors. 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. Life Sci. Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective. doi:10.1074/jbc.274.18.12431, Schlagenhauf, P., Grobusch, M. P., Maier, J. D., and Gautret, P. (2020). Res. Proc. RAS, especially several cleavage products of the peptide angiotensin (AGT) along with their receptors, maintains a balance of fluid volume and pressure. doi:10.1165/ajrcmb.20.5.3382, Pascarella, G., Strumia, A., Piliego, C., Bruno, F., Del Buono, R., Costa, F., et al. The functional inhibition of relevant lung enzymes and ion channels may disturb AFC, thus resulting pulmonary edema in COVID-19 patients. CFTR inhibitors, like glibenclamide and CFTRinh-172 inhibitor, distinctly reduced absorptive alveolar fluid transport (Solymosi et al., 2013). No use, distribution or reproduction is permitted which does not comply with these terms. 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). doi:10.1161/01.cir.96.6.1847. Perplexingly, among the currently pursued therapeutic strategies against COVID-19, none is designed to directly protect the alveolo-capillary barrier. Natural compounds can inhibit the binding between the virus and the ACE2 receptor of host cells. Invited Review: Active Fluid Clearance from the Distal Air Spaces of the Lung. N. Engl. doi:10.1136/bmj.m1432, Fleckenstein, A. Med. CFTR and NKCC inhibitors show promise in treating pulmonary edema. EBioMedicine. (2016). Sci. 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). Traditional Chinese Medicine for COVID-19 Treatment. Natl. doi:10.1152/physrev.1974.54.3.678, Steinritz, D., Stenger, B., Dietrich, A., Gudermann, T., and Popp, T. (2018). Thus, PGs play a key role in the formation of pulmonary edema. Pulmonary capillary leak syndrome following COVID-19 virus infection Pulmonary edema - Diagnosis and treatment - Mayo Clinic Rev. 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. 383, 23332344. (2019). J. Med. 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. Vaccination of Adults with Lung Disease Including Asthma | CDC Lianhuaqingwen Exerts Anti-viral and Anti-inflammatory Activity against Novel Coronavirus (SARS-CoV-2). HA is synthesized by HAS2. DD&T 14 (5), 256258. In these patients, white blood cells count, neutrophil count and D-dimer level keep rising while lymphocyte count keeps decreasing as the disease progresses. 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. 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. J. Biol. Am. 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). 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. Eur. doi:10.1111/joim.13091, Passi, A., Negrini, D., Albertini, R., de Luca, G., and Miserocchi, G. (1998). Clin. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19). Annu. doi:10.1146/annurev-virology-110615-042301, Li, L., Zhang, W., Hu, Y., Tong, X., Zheng, S., Yang, J., et al. 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. Infection, pulmonary edema, lung cancer, aspiration, and pulmonary hemorrhage are some of the diseases that can cause consolidation. FIGURE 6. (2021). Epub 2020 Jun 29. 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). Acad. Am. Cel Mol Biol 28 (3), 363372. J. Biol. AQP-5 protein, present in the apical membranes of AT-I cell of alveolar epithelium, can regulate the transport of water molecules. Semin. J. Biol. A vision of coronavirus with the minimal set of structural proteins. FOIA For patients recovering from COVID-19 who have persistent, progressive, or new respiratory symptoms, we obtain PFTs including spirometry, lung volumes, and diffusion capacity. Pharmacol. TABLE 1. Several cases of vaccine-induced thrombotic thrombocytopenia from a similar viral vector vaccine (Oxford-AstraZeneca [ChAdOx1 nCoV-19]) have been reported. Med. Med. Chinese Medicine (TCMs), already widely used in China, may also be beneficial in addressing pulmonary edema in COVID-19 patients (Zhang et al., 2020; Yang et al., 2020d). Care Med. Mechanism of inhibiting ENaC inducing pulmonary edema. 225 (4), 618627. doi:10.1203/00006450-199908000-00014, Christ-Crain, M., Hoorn, E. J., Sherlock, M., Thompson, C. J., and Wass, J. 34 (4), 610618. Myocarditis, Pulmonary Hemorrhage, and Extensive Myositis with Sci. (1986). Nature 590, 635641. doi:10.1056/NEJMoa2028836, Tang, Y., Liu, J., Zhang, D., Xu, Z., Ji, J., and Wen, C. 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Patients receive high-flow nasal cannula (HFNC), non-invasive ventilation (NIV), mechanical ventilation or ECMO as respiratory supports (Guo et al., 2020; Pascarella et al., 2020), a crystalloid fluid to ensure body fluid equilibrium (Christ-Crain et al., 2020), and anticoagulants for restraining the thrombus formation to aid in circulatory support (Connors and Levy, 2020). Res. 8 (8), 807815. Available: http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml (Accessed February 4, 2021). Rev. COVID-19 Vaccination-related Lymphadenopathy: What To Be Aware Of Bethesda, MD 20894, Web Policies 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. 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. Dis. Diagnostics | Free Full-Text | The Role of Cardiac Biomarkers in the 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). Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment 2, 26372646. Physiol. Br. 158 (6), 16211628. (2020). Side effects of the coronavirus vaccines | NHS inform COVID-19 vaccination may cause acute IPF exacerbation - Healio Coronavirus Disease 2019 Treatment A Review of Early and Emerging Options. 80 (4), 394400. Water and sodium disturbances along with the unusual serum potassium levels are most common. Physiol. 104, 81125. In addition, HA is a part of a three-dimensional matrix in pulmonary interstitial, which consists of HA, PGs and fibrillar macromolecules providing resistance to tissue compression and interstitial fluid expansion (Negrini et al., 2008).When PGs and HA interact with collagen IV, a fibrillar macromolecule modulating capillary permeability in the vascular basement membrane, the compound substance limit fluid influx into the interstitium. Kiener M, Roldan N, Machahua C, Sengupta A, Geiser T, Guenat OT, Funke-Chambour M, Hobi N, Kruithof-de Julio M. Front Med (Lausanne). Pharmacol. CD44-dependent Intracellular and Extracellular Catabolism of Hyaluronic Acid by Hyaluronidase-1 and -2. BMJ 369, m1432. 291 (6), L1207L1219. Semin. Preprint. As the infection progresses, the immune function is impaired, causing damage to multiple organs, additional complications, and eventually death (Yang et al., 2020). 33, 258269. Glucocorticoid Induction of Epithelial Sodium Channel Expression in Lung and Renal Epithelia Occurs via Trans-activation of a Hormone Response Element in the 5-Flanking Region of the Human Epithelial Sodium Channel Subunit Gene. 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. 274 (18), 1243112437. 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). 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). Woman dies half an hour after vaccine: Autopsy shows pulmonary edema So far, only remdesivir was approved by FDA for the compassionate use in severe infected COVID-19 patients (Beigel et al., 2020). Symptoms that are common to all of these conditions include cough and shortness of breath. This site needs JavaScript to work properly. The spike (S) protein of coronavirus, one of the surface glycoproteins, is divided into two functional units, S1 and S2. 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). 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. XC analyzed and reviewed the research articles as well as drafting the manuscript. Chansu Injection Improves the Respiratory Function of Severe COVID-19 Patients. It has been shown that the incidence and severity of COVID-19 are closely related to abnormal metabolism of inorganic salts. Authors Mabrouk Bahloul 1 . When to. 157, 104882. doi:10.1016/j.phrs.2020.104882, Zhang, H., and Baker, A. Blood 135 (23), 20332040. doi:10.1126/scitranslmed.3004276, Towne, J. E., Krane, C. M., Bachurski, C. J., and Menon, A. G. (2001). Ann. doi:10.1111/j.1440-1827.2004.01754.x, Garvin, M. R., Alvarez, C., Miller, J. I., Prates, E. T., Walker, A. M., Amos, B. K., et al. Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on 2 -Adrenergic Receptor Signaling. (2020). 388 (4), 421436. 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. Some natural compounds along with their antiviral and reducing pulmonary edema mechanisms are shown in Table 2. Lancet Respir. COVID-19 Vaccine FAQ | American Lung Association Technol. 276 (22), 1865718664. 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. J. Physiology-Lung Cell Mol. 161, 105290. doi:10.1016/j.phrs.2020.105290, Shi, Y., Wang, Y., Shao, C., Huang, J., Gan, J., Huang, X., et al. Invest. 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). Endocrinology in the Time of COVID-19: Management of Diabetes Insipidus and Hyponatraemia. (1999). Pharmacol. We identified pulmonary edema, pleural effusion, and pericardial effusion. The abnormal humoral metabolism and pulmonary edema contribute to the severity of symptoms and fatality of COVID-19 patients. A., and Cook, D. I. 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. 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 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. Res. (2017). Crit. Mol. Front Pharmacol. Evolution of the Novel Coronavirus from the Ongoing Wuhan Outbreak and Modeling of its Spike Protein for Risk of Human Transmission. Nat. 21, 97S107S. Am. Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control. The Role of Proteoglycans in Pulmonaryedema Development. Accessibility Dexamethasone for the Treatment of Coronavirus Disease (COVID-19): a Review. The COVID-19 Vaccine Development Landscape. doi:10.1056/NEJMoa2007764, Bessac, B. F., and Jordt, S.-E. (2008). Sodium transport is the main ion transport involved in the AFC. Exp. Res. Inhibiting the inflammatory storm can effectively alleviate pulmonary edema. Potassium channels up-regulate ENaC expression via activating KvLQT1 pathway so as to control AFC (Bardou et al., 2012). doi:10.1182/blood.2020006000, Couto, M., de Diego, A., Perpii, M., Delgado, L., and Moreira, A. doi:10.1007/s00018-007-6228-6, Itani, O. J. Pract. doi:10.1016/s2213-2600(20)30225-3, Goldenberg, N. M., Ravindran, K., and Kuebler, W. M. (2015). He had no cough, expectoration, nasal discharge or sore throat. Efficacy and Safety of Garadacimab in Combination with Standard of Care Treatment in Patients with Severe COVID-19. Med. Pfizer-BioNTech COVID-19 Vaccine Reactions & Adverse Events 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). 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. 1, 2 More recently, six cases of. Infection and replication process of SARS-CoV-2. Hemost. Pulmonary Edema in COVID-19: Explained by Bradykinin?. Circ. Limmer A, Engler A, Kattner S, Gregorius J, Pattberg KT, Schulz R, Schwab J, Roth J, Vogl T, Krawczyk A, Witzke O, Zelinskyy G, Dittmer U, Brenner T, Berger MM. (2020). 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).