JAMA 324 (5), 460470. medRxiv. Pharmacol. doi:10.1007/s00018-007-6228-6, Itani, O. TGF--induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. 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). Some natural compounds along with their antiviral and reducing pulmonary edema mechanisms are shown in Table 2. The secretion of alveolar fluid, caused by inhibiting Na+ entry, is sensitive to inhibition of CFTR, NKCC, or Na+-K+-ATPase (Solymosi et al., 2013), suggesting that CFTR, NKCC or Na+-K+-ATPase inhibitors may have potential in treating pulmonary edema caused by low expression of ENaC. Response of Thiazide-Induced Hypokalemia to Amiloride. SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis. 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. (2020c). Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma. However, the efficacy and safety of these drugs in COVID-19 patients are unclear. Further, ARDS is sometimes initially diagnosed as pneumonia or pulmonary edema (fluid in the lungs from heart disease). In these patients, white blood cells count, neutrophil count and D-dimer level keep rising while lymphocyte count keeps decreasing as the disease progresses. 156, 104761. doi:10.1016/j.phrs.2020.104761, Sartori, C., Allemann, Y., Duplain, H., Lepori, M., Egli, M., Lipp, E., et al. Lancet Respir. 2023 Feb 14;14:1080962. doi: 10.3389/fphar.2023.1080962. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 291 (6), L1207L1219. doi:10.1073/pnas.160041997, Leroy, C., Priv, A., Bourret, J.-C., Berthiaume, Y., Ferraro, P., and Brochiero, E. (2006). Influenza Virus Inhibits Amiloride-Sensitive Na+ Channels in Respiratory Epithelia. 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). COVID19 Diagnosis and Management: a Comprehensive Review. J. 308 (11), L1178L1188. Res. Cel Mol Biol 54 (3), 370383. Bradykinin (BK) is an important cellular mediator that causes vasodilatation and leaky blood vessels, leading to vascular leakage and edema (de Maat et al., 2020). Front. doi:10.1165/rcmb.2002-0101OC, Kaneko, Y., and Szallasi, A. Cel Mol Biol 20 (5), 10281040. ), cell growth and death, as well as the degradation of damaged cells (Zhao et al., 2020). The abnormal humoral metabolism and pulmonary edema contribute to the severity of symptoms and fatality of COVID-19 patients. 8 (4), 420422. COVID-19 and its Implications for Thrombosis and Anticoagulation. 108 (6), 11851194. Physiol. Moreover, other drugs which can regulate immune system like hydroxychloroquine and azithromycin may also show effects in treating SARS-COV-2-induced pulmonary edema and their effectiveness in treating SARS-COV-2 infections should be further investigated. The activities of the molecules in RAS are ruled by dynamic changes responding to an injury. The clinical manifestations and CT scans show the presence of ARDS in critical COVID-19 patients (Ai et al., 2020; Guan et al., 2020; Huang 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. 12:664349. doi: 10.3389/fphar.2021.664349. 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). 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). (2020). doi:10.5582/ddt.2020.03070, Ahmed, M. H., and Hassan, A. First, we could not entirely rule out infection, but results of blood cultures and COVID-19 testing were negative. Several cases of vaccine-induced thrombotic thrombocytopenia from a similar viral vector vaccine (Oxford-AstraZeneca [ChAdOx1 nCoV-19]) have been reported. Sodium transport is the main ion transport involved in the AFC. doi:10.1016/j.bbamem.2012.02.025, Bartoszewski, R., Matalon, S., and Collawn, J. F. (2017). Other anti-viral drugs, such as arbidol, chloroquine phosphate and ritonavir, did not exhibit efficacy in randomized, placebo-controlled trials in COVID-19 patients. Pharmacol. COVID-19 can cause blood clots, even months after diagnosis. Also, thrombocytopenia and thrombosis have been mostly reported after AstraZeneca (ChAdOx1 nCoV-19) and Johnson & Johnson/Janssen COVID-19 vaccines [ 3 ]. Chem. Physiol. COVID-19 Vaccine: A Comprehensive Status Report. The Serum and Glucocorticoid Kinase Sgk Increases the Abundance of Epithelial Sodium Channels in the Plasma Membrane of Xenopus Oocytes. (2020). (1986). (2017). Physiol. doi:10.1177/0004563220922255, Liu, Y., Huang, F., Xu, J., Yang, P., Qin, Y., Cao, M., et al. Effect and Mechanism of Astragaloside A on Acute Respiratory Failure in Rats. B., et al. Phytomedicine 85, 153282. doi:10.1016/j.phymed.2020.153282, Ma, Q., Pan, W., Li, R., Liu, B., Li, C., Xie, Y., et al. Among the currently pursued therapeutic strategies against COVID-19, little attention has been paid to abnormal lung humoral metabolism. 2, 26372646. 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. 2022 Dec;134:102427. doi: 10.1016/j.artmed.2022.102427. Physiol. 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. (2021). Repurposing of Clinically Approved Drugs for Treatment of Coronavirus Disease 2019 in a 2019-novel Coronavirus-Related Coronavirus Model. Transient Receptor Potential (TRP) Channels: a Clinical Perspective. FIGURE 3. Mechanism of BK inducing pulmonary edema and potential drugs. Potential drugs for normalizing humoral metabolism. doi:10.1002/jmv.25848, Cutts, S., Talboys, R., Paspula, C., Prempeh, E., Fanous, R., and Ail, D. (2017). Lung Cel Mol Physiol 282, L631L641. Studies showed that ENaC activators or stimulators can regulate ENaC-dependent fluid absorption in alveolar and pulmonary edema (Fronius, 2013). 10.1101/2020.02.13.20022673 Pharmacol. 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. Inhibiting the inflammatory storm can effectively alleviate pulmonary edema. Pharmacol. However, clinical evidence showing that glucocorticoids can reduce pulmonary edema by regulating fluid absorption in alveolar and glucocorticoids is missing. J. Pract. Negative-feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-dependent Regulation of Transient Receptor Potential Vanilloid 4. J. Respir. Diagnosing COVID-19: The Disease and Tools for Detection. 183 (1), G9G15. Pulmonary Fibrosis and COVID-19: the Potential Role for Antifibrotic Therapy. JAMA 323 (20), 20522059. [Med. TABLE 1. 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. FIGURE 5. Would you like email updates of new search results? doi:10.1097/CM9.0000000000000797, Ferner, R. E., and Aronson, J. K. (2020). (2006) reported that the cryptotanshinone in Salvia miltiorrhiz can inhibit the synthesis of cGMP and NO in vein endothelial cells, activate NO/cGMP pathway and improve the blood circulation. 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. 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). 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). 308 (11), L1136L1144. Pulmonary Edema in COVID-19: Explained by Bradykinin?. Thus, PGs play a key role in the formation of pulmonary edema. (2015). Additionally, other major ADRs were potentially linked to the BNT162b2 mRNA COVID-19 vaccine, including central nervous system thrombosis, deep vein thrombosis, and pulmonary embolism [3-5]. Natl. Gut 69 (6), 10101018. Rev. Thromb. 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). The Current Evidence for the Treatment of Sepsis with Xuebijing Injection: Bioactive Constituents, Findings of Clinical Studies and Potential Mechanisms. Cells 7 (8), 98. doi:10.3390/cells7080098, Stone, J. H., Frigault, M. J., Serling-Boyd, N. J., Fernandes, A. D., Harvey, L., Foulkes, A. S., et al. Original Article Antibody Responses to Haemophilus influenzae Type b Vaccines in Men with Human . Abnormal humoral metabolism is mainly manifested as imbalances of water and electrolytes. eCollection 2021. (1999). Technol. AQP-5 plays a significant role in pulmonary edema and decreased expression of AQP-5 has been observed during the disease process. Physiol. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. It has been shown that the incidence and severity of COVID-19 are closely related to abnormal metabolism of inorganic salts. Int. 46 (2), 208214. 8600 Rockville Pike (2018). Med. Int. 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. Care Med. 157, 104820. doi:10.1016/j.phrs.2020.104820, Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J. a., Liu, H., et al. doi:10.1182/blood.2020006000, Couto, M., de Diego, A., Perpii, M., Delgado, L., and Moreira, A. A., et al. 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. -, Adil M. S., Narayanan S. P., Somanath P. R. (2020). Aquaporins in the Lung. XC analyzed and reviewed the research articles as well as drafting the manuscript. FIGURE 4. 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). 35 (19), 30142017. doi:10.1136/gutjnl-2020-320953, Zhang, J.-L., Zhuo, X.-J., Lin, J., Luo, L.-C., Ying, W.-Y., Xie, X., et al. Aldosterone-induced Sgk1 Relieves Dot1a-Af9-Mediated Transcriptional Repression of Epithelial Na+ Channel . J. Clin. Am. doi:10.1056/NEJMoa2007764, Bessac, B. F., and Jordt, S.-E. (2008). Optimizing Diagnostic Strategy for Novel Coronavirus Pneumonia, a Multi-center Study in Eastern China. Can COVID-19 cause pulmonary embolism? Acta (Bba) - Biomembranes 1818 (7), 16821690. Immunol. Certain vaccine-preventable diseases can also increase swelling of your airways and lungs. Arek Sarkissian. Decreased Expression of Aquaporin-5 in Bleomycin-Induced Lung Fibrosis in the Mouse fibrosis in the Mouse. J. Respir. Diagn Pathol. The condition presents itself as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and alveolar edema (Xu et al., 2020; Wiersinga et al., 2020). 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.00395.2015, Birrell, M. A., Belvisi, M. G., Grace, M., Sadofsky, L., Faruqi, S., Hele, D. J., et al. -, Ai J.-W., Zhang H.-C., Xu T., Wu J., Zhu M., Yu Y.-Q., et al. 2021 May 7;8:644678. doi: 10.3389/fmed.2021.644678. Sci. 1480 (1), 73103. 103, 7888. 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). With treatment, most people with this type of pulmonary edema recover in about 24 hours. 275(3), L631L635. 180 (11), 10421047. (2012). Calcium Antagonists and Their Mode of Action: an Historical Overview. Am. 160, 105073. doi:10.1016/j.phrs.2020.105073, Maronde, R. F., Milgrom, M., Vlachakis, N. D., and Chan, L. (1983). Rhinovirus Upregulates Transient Receptor Potential Channels in a Human Neuronal Cell Line: Implications for Respiratory Virus-Induced Cough Reflex Sensitivity. doi:10.1007/s11427-020-1637-5, Xu, Y.-H., Dong, J.-H., An, W.-M., Lv, X.-Y., Yin, X.-P., Zhang, J.-Z., et al. (Engl) 133 (9), 10511056. COVID-19 can cause lung complications such as pneumonia and, in the most severe cases, acute respiratory distress syndrome, or ARDS . Circulation 37 (1), 4553. (2005). See this image and copyright information in PMC. Circ. The structure of coronavirus (Figure 1 A vision of coronavirus with the minimal set of structural proteins.) (2019). doi:10.1136/thoraxjnl-2013-203894, PubMed Abstract | CrossRef Full Text | Google Scholar, Achanta, S., and Jordt, S. E. (2020). Med. Pharmacol. Dis. Endocrinology in the Time of COVID-19: Management of Diabetes Insipidus and Hyponatraemia. Biochim. (2019). 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). Moreover, lower expression of alveolar Na-K-ATPase promotes pulmonary edema, and when the expression of Na-K-ATPase 1- and 2-subunits decreases, maximal alveolar epithelial fluid clearance is reduced (Looney et al., 2005). doi:10.1073/pnas.1216382110, Staub, N. C. (1974). 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). Heart Circ. 7 (4). (2020). [Effect of Astragali Radix in Improving Early Renal Damage in Metabolic Syndrome Rats through ACE2/Mas Pathway]. 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). Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients. (2020b). doi:10.1161/01.cir.96.6.1847. Pulmonary Edema. Res. 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). Med. Treatment of Pulmonary Edema by ENaC Activators/Stimulators. Purpose To investigate pulmonary vascular abnormalities at CT pulmonary angiography (CT-PE) in patients with coronavirus disease 2019 (COVID-19) pneumonia. doi:10.1001/jama.2020.10044, Lippi, G., South, A. M., and Henry, B. M. (2020). Respir. When to. Role of Drugs Used for Chronic Disease Management on Susceptibility and Severity of COVID19: A Large CaseControl Study. 46 (7), 835837. Pharmacol. 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Unable to load your collection due to an error, Unable to load your delegates due to an error. 10.5582/ddt.2020.03070 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. Oxygen flows through a face mask or a flexible plastic tube with two openings (nasal cannula) that deliver oxygen to each nostril. The .gov means its official. Science 367 (6485), 14441448. doi:10.1016/j.bbagen.2005.09.009, Zhuo, X.-J., Hao, Y., Cao, F., Yan, S.-F., Li, H., Wang, Q., et al. Pharmacol. 173 (3), 281287. J. Physiology-Lung Cell Mol. doi:10.1161/01.RES.0000247065.11756.19, Andr, E., Gatti, R., Trevisani, M., Preti, D., Baraldi, P., Patacchini, R., et al. There are also several natural compounds which were previously shown to have positive effects on the lung edema-associated targets described in this paper (Zhou et al., 2006; Ho et al., 2007; Ji et al., 2014; Wang et al., 2015; Qu, 2019; Fan et al., 2020; Lung et al., 2020). Lung Injury in COVID-19 Has Pulmonary Edema as an Important Component and Treatment with Furosemide and Negative Fluid Balance (NEGBAL) Decreases Mortality. Ion channels, AQPs, RAS, bradykinin and hyaluronic acid are factors influencing the pulmonary edema. Naunyn-schmiedeberg's Arch. Qu, G. J. N. Engl. Infection and replication process of SARS-CoV-2. Med. (2008). (2018). (2020). These cytokine storms can be treated with steroids, IL-1 antagonists, TNF inhibitors, and Janus kinase inhibitor (JAK) inhibitors (McCreary and Pogue, 2020). 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. Therefore, drugs targeted at the humoral mechanisms might turn out to be highly effective against SARS-COV-2 infections. 288, 198114. doi:10.1016/j.virusres.2020.198114, Krlicka, A. L., Kruczkowska, A., Krajewska, M., and Kusztal, M. A. JAMA 324 (8), 782793. 54 (10), 774780. 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. J. (2020b). Association between Early Treatment with Qingfei Paidu Decoction and Favorable Clinical Outcomes in Patients with COVID-19: A Retrospective Multicenter Cohort Study. J. Nat. A., Auerbach, S. D., Husted, R. F., Volk, K. A., Ageloff, S., Knepper, M. A., et al. J. Huazhong Univ. Sci. (2000). Zhang J, Zhou N, Wang Y, Liu T, Cao Y, Feng W, Zheng X. Focusing on decreasing the formation of body fluid in lung or promoting the absorption of body fluid can contribute to a decrease in lung damage and decreased mortality in COVID-19 patients. Allergol. HM designed the framework of the review. doi:10.1007/s11596-015-1490-6, Jovanovi, S., Crawford, R. M., Ranki, H. J., and Jovanovi, A. Annu. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Res. Transl. doi:10.1093/ofid/ofaa105/5811022, Minakata, Y., Suzuki, S., Grygorczyk, C., Dagenais, A., and Berthiaume, Y. (2020). (2020a). Patients with SARS-CoV-2-Induced Viral Sepsis Simultaneously Show Immune Activation, Impaired Immune Function and a Procoagulatory Disease State. 274 (18), 1243112437. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-Threatening COVID-19. (2016). Among the currently pursued therapeutic strategies against COVID-19, little attention has been paid to abnormal lung humoral metabolism. doi:10.1016/bs.apcsb.2015.11.005, Cure, E., and Cumhur Cure, M. (2020). Crit. Chem. 313 (5), L859L872. However, palpable lymphadenopathy commonly involving the axilla as an immune response to vaccination may present a clinical diagnostic dilemma especially in persons with . Glucocorticoids, especially dexamethasone, have already been applied in the clinical treatment of COVID-19. J. Infect. Please enable it to take advantage of the complete set of features! Sci. TRPA1 Agonists Evoke Coughing in guinea Pig and Human Volunteers. As RAS plays an important role in PFC and AFC, astragaloside IV from Astragalus propinquus is able to protect kidney and respiratory by activating the ACE2-Ang-(17)-Mas pathway in RAS and improving ACE2, Ang-(17), Mas level (Wang et l., 2015; Qu, 2019). COVID-19, an infectious disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a global reach. Res. doi:10.1146/annurev.pa.17.040177.001053, Fronius, M. (2013).
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