Consequently, the use of bradykinin antagonists is supposed to be regarded as a strategy for COVID-19 treatment interventions. The likelihood of hypertensive patients developing COVID-19, who were treated by ARBs, was reported to decrease by 76% (Yan et al., 2020). Exp. 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). (1997). 46 (2), 208214. 471 (4), 519532. Am. 274 (53), 3783437839. 2020 Aug 14;15(1):103. doi: 10.1186/s13000-020-01017-8. doi:10.1073/pnas.1216382110, Staub, N. C. (1974). 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). 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. Reaffirms recommendation for Janssen COVID-19 Vaccine. Some natural compounds along with their antiviral and reducing pulmonary edema mechanisms are shown in Table 2. Pharmacol. Am. Crit. Front Pharmacol. It shows the vaccine is teaching your body's immune system how to protect itself from the disease. Med. ), cell growth and death, as well as the degradation of damaged cells (Zhao et al., 2020). (2021). J. Physiol. medRxiv.doi:10.1101/2020.05.20.20107607, Hu, K., Guan, W.-j., Bi, Y., Zhang, W., Li, L., Zhang, B., et al. 33, 258269. doi:10.1007/s42399-020-00610-8, Ai, J.-W., Zhang, H.-C., Xu, T., Wu, J., Zhu, M., Yu, Y.-Q., et al. (2015). It not only can induce de novo synthesis of ENaC and affect ENaC regulatory pathway, but also has an impact on cytokines. Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Usage Is Associated with Improved Inflammatory Status and Clinical Outcomes in COVID-19 Patients with Hypertension. (2014). 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). Ijerph 17 (15), 5320. doi:10.3390/ijerph17155320, Kunzelmann, K., Beesley, A. H., King, N. J., Karupiah, G., Young, J. Protectin DX Increases Alveolar Fluid Clearance in Rats with Lipopolysaccharide-Induced Acute Lung Injury. government site. J. Med. 2 3 Postauthorisation reports of severe reactions, including anaphylaxis, have been extremely rare, occurring in only 4.5 reported cases per million doses. 276 (22), 1865718664. 282 (8), 55975607. 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. The toad venom injection can significantly improve the pulmonary function of COVID-19 patients by regulating PaO2/FiO2 and ROX index and thus alleviate pulmonary edema. 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). Copyright 2021 Cui, Chen, Zhou, Gong, Zhu, Lv, Guo, Duan, Zhou, Marcon and Ma. doi:10.1152/ajplung.1998.275.3.L631, Perkins, G. D., McAuley, D. F., Thickett, D. R., and Gao, F. (2006). Elevated pulmonary venous pressure leads to faster fluid infiltration into the interstitial lung than the ability of the pulmonary lymphatic vessel to drain away fluid, resulting in pulmonary edema. 10.1136/thoraxjnl-2013-203894 -. Ion Channels of the Lung and Their Role in Disease Pathogenesis. doi:10.1001/jama.2020.10044, Lippi, G., South, A. M., and Henry, B. M. (2020). 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). Chloroquine and Hydroxychloroquine in Covid-19. 102 (8), 966974. Transient Receptor Potential (TRP) Channels: a Clinical Perspective. (2015). It is likely that alveolar fluid clearance (AFC) failure plays a major role in the pathogenesis of pulmonary edema. 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. The activation of -adrenergic receptor, especially 2 (Mutlu et al., 2004), was found to stimulate Na+ and fluid reabsorption. Serum sodium shows a decrease trend in CODIV-19 development (Krolicka et al., 2020). Clin. 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). Who (2021). Wiersinga, W. J., Rhodes, A., Cheng, A. C., Peacock, S. J., and Prescott, H. C. (2020). Dis. (2018). The available adenoviral vaccines appear to stimulate autoantibodies to platelet factor 4 (PF4), which . Diagnosing COVID-19: The Disease and Tools for Detection. Clipboard, Search History, and several other advanced features are temporarily unavailable. Chem. 2023 Feb 15;12(4):1542. doi: 10.3390/jcm12041542. Circuits between Infected Macrophages and T Cells in SARS-CoV-2 Pneumonia. You might run a fever and experience body aches, headaches and tiredness for a day or two. doi:10.1074/jbc.274.53.37834, De Logu, F., Patacchini, R., Fontana, G., and Geppetti, P. (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). Also, thrombocytopenia and thrombosis have been mostly reported after AstraZeneca (ChAdOx1 nCoV-19) and Johnson & Johnson/Janssen COVID-19 vaccines [ 3 ]. 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. 2023 Feb 14;14:1080962. doi: 10.3389/fphar.2023.1080962. 35 (19), 30142017. Water and sodium disturbances along with the unusual serum potassium levels are most common. 39 (270), H2000H2007. doi:10.1165/rcmb.2002-0101OC, Kaneko, Y., and Szallasi, A. Am. Res. 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). 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. It is worth mentioning that, except alveoli, which is widely known as the target tissue, cardiomyocyte can be infected as well. Ursodeoxycholic Acid Stimulates Alveolar Fluid Clearance in LPSinduced Pulmonary Edema via ALX/cAMP/PI3K Pathway. Pharmacol. (2020b). Med. Infect. A., and Cook, D. I. Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on 2 -Adrenergic Receptor Signaling. FIGURE 6. (2020). Electrolyte Imbalances in Patients with Severe Coronavirus Disease 2019 (COVID-19). 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. 2022 Dec;134:102427. doi: 10.1016/j.artmed.2022.102427. 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. Physiol. doi:10.1146/annurev.pa.17.040177.001053, Fronius, M. (2013). Am. Chem. Combination Therapy with Cystic Fibrosis Transmembrane Conductance Regulator Modulators Augment the Airway Functional Microanatomy. 158 (6), 16211628. doi:10.1152/ajplung.00244.2017, Looney, M. R., Sartori, C., Chakraborty, S., James, P. F., Lingrel, J. Potassium channels up-regulate ENaC expression via activating KvLQT1 pathway so as to control AFC (Bardou et al., 2012). J. Pract. 10.1007/s42399-020-00610-8 doi:10.1146/annurev-virology-110615-042301, Li, L., Zhang, W., Hu, Y., Tong, X., Zheng, S., Yang, J., et al. medRxiv. J. Cel Physiol 235 (12), 95109523. doi:10.1073/pnas.96.5.2514, Chow, Y.-H., Wang, Y., Plumb, J., O'Brodovich, H., and Hu, J. Chills and swollen lymph nodes can also occur. Besides those direct causes of COVID-19 pulmonary edema, there are other factors that can be described as abnormal humoral metabolism which can influence the AFC and PFC, resulting the manifestation of pulmonary edema (Figure 3 Cause of COVID-19 pulmonary edema). 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. Allergy Clin. 10.1111/nyas.14472 JAMA 323 (11), 10611069. Before 158, 104850. doi:10.1016/j.phrs.2020.104850, Ma, Q., Qiu, M., Zhou, H., Chen, J., Yang, X., Deng, Z., et al. 192 (8), 37653777. This site needs JavaScript to work properly. (2011). B., van der Loos, C. M., et al. 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. TGF--induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. (2003). HA-related hydrogel has been found in both, ARDS and SARS. The site is secure. As such, TRPV4 inhibition likely has protective and beneficial effect on mucus clearance and pulmonary edema. doi:10.1038/s41418-020-0530-3, Shi, Z., Ye, W., Zhang, J., Zhang, F., Yu, D., Yu, H., et al. (2004). Nonetheless, little attention has been paid to CD44 in COVID-19 treatment. Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control. Perplexingly, among the currently pursued therapeutic strategies against COVID-19, none is designed to directly protect the alveolo-capillary barrier. It promotes the clearance of surplus fluid in alveoli and keeps alveolar space dry (Wittekindt and Dietl, 2019). TABLE 2. However, so far, no effective inhibitors have been developed against HAS2. (2018). Gut 69 (6), 10101018. Pathological Findings of COVID-19 Associated with Acute Respiratory Distress Syndrome. J. Physiology-Lung Cell Mol. 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. Physiol. CFTR inhibitors, like glibenclamide and CFTRinh-172 inhibitor, distinctly reduced absorptive alveolar fluid transport (Solymosi et al., 2013). Biochem. Fondazione Salvatore Maugeri (IRCCS), Italy. doi:10.1126/scitranslmed.3004276, Towne, J. E., Krane, C. M., Bachurski, C. J., and Menon, A. G. (2001). It has been shown that the incidence and severity of COVID-19 are closely related to abnormal metabolism of inorganic salts. 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. Regardless, it seems reasonable that antiviral therapy might be adopted to patients with high risk factors as early as possible rather than wait for severe manifestation of the disease. Remdesivir for the Treatment of Covid-19 - Final Report. 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. Lancet Respir. Hyponatremia in Infectious Diseases-A Literature Review. J. Physiology-Lung Cell Mol. 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). (1999). N.Y. Acad. Sharma, A., Garcia, G., Wang, Y., Plummer, J. T., Morizono, K., Arumugaswami, V., et al. Chem. FOIA A., et al. Regulation of ENaC and CFTR Expression with K+ Channel Modulators and Effect on Fluid Absorption across Alveolar Epithelial Cells. Some others will likely be approved soon (Kaur and Gupta, 2020; Thanh Le et al., 2020). CDC interim clinical considerations and FDA doi:10.1152/ajplung.00085.2001, Ito, Y., Correll, K., Zemans, R. L., Leslie, C. C., Murphy, R. C., and Mason, R. J. eCollection 2021. Am. (2013). Salmeterol for the Prevention of High-Altitude Pulmonary Edema. 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. Ther. PMC Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-Threatening COVID-19. Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. Physiology 23, 360370. (2012). 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). (2020). doi:10.1073/pnas.160041997, Leroy, C., Priv, A., Bourret, J.-C., Berthiaume, Y., Ferraro, P., and Brochiero, E. (2006). First post-authorization U.S. doses of Janssen COVID -19 Vaccine. Physiol. J. Respir. (2020a). doi:10.3969/j.issn.10065725.2019.19.008, Rasaeifar, B., Gomez-Gutierrez, P., and Perez, J. J. 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. 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. TRPs are essential for the respiratory system and pulmonary edema, in which TRPA1, TRPV1 and TRPV4 are the most important. doi:10.1038/s12276-018-0075-4, Zwaveling, S., Gerth van Wijk, R., and Karim, F. (2020). J. Physiol. IL6 monoclonal antibody or tocilizumab was thought to work by interrupting inflammatory storm after the infection, but the latest clinical study published in NEJM showed that Tocilizumab was not effective in preventing intubation or death in mild hospitalized COVID-19 patients (Stone et al., 2020). 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. Rev. Summary of potential natural compounds against COVID-19. Circ. Original Article Antibody Responses to Haemophilus influenzae Type b Vaccines in Men with Human . Response of Thiazide-Induced Hypokalemia to Amiloride. North America 33 (4), 869889. 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. Potential drugs for normalizing humoral metabolism. 288, 198114. doi:10.1016/j.virusres.2020.198114, Krlicka, A. L., Kruczkowska, A., Krajewska, M., and Kusztal, M. A. doi:10.1101/2020.03.20.20039586, Londino, J. D., Lazrak, A., Collawn, J. F., Bebok, Z., Harrod, K. S., and Matalon, S. (2017). (1986). (2013). Careers. et al., 2020). 156, 104761. doi:10.1016/j.phrs.2020.104761, Sartori, C., Allemann, Y., Duplain, H., Lepori, M., Egli, M., Lipp, E., et al. doi:10.1016/j.cmet.2021.01.002, Chen, S.-y., Bhargava, A., Mastroberardino, L., Meijer, O. C., Wang, J., Buse, P., et al. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. doi:10.1038/labinvest.2016.150, Zhang, P. h., Han, J., Cao, F., Liu, Y. j., Tian, C., Wu, C. h., et al. 2023 Apr;201(2):159-170. doi: 10.1007/s00408-023-00615-9. Invited Review: Active Fluid Clearance from the Distal Air Spaces of the Lung. Mol. doi:10.1172/JCI29850, Zhao, J., Tian, S., Lu, D., Yang, J., Zeng, H., Zhang, F., et al. Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective. Exuberant Elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 Infection Is Associated with Disease Severity and Fatal Outcome. Med. Mechanism of inhibiting ENaC inducing pulmonary edema. J. Clin. 1480 (1), 73103. J. Nat. Multiple TCMs have been already clinical applied for COVID-19 in China and achieved high recovery rate. Furosemide, a NKCC inhibitor, has been acknowledged as first-line therapeutic drug for pulmonary edema all the time (Pickkers et al., 1997; Solymosi et al., 2013). 103, 7888. A health care provider monitors the oxygen level. Repurposing Antimalarials and Other Drugs for COVID-19. Immune-modulatory agents for COVID-19 include tocilizumab, human immunoglobulin and the convalescent plasma. Cel Mol Biol 20 (5), 10281040. Bookshelf Structure and Hormone Responsiveness of the Gene Encoding the -Subunit of the Rat Amiloride-Sensitive Epithelial Sodium Channel. (2012). Res. (2020). Therefore, drugs targeted at the humoral mechanisms might turn out to be highly effective against SARS-COV-2 infections.

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