Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential

Xinyu Cui, Wuyue Chen, Haoyan Zhou, Yuan Gong, Bowen Zhu, Xiang Lv, Hongbo Guo, Jinao Duan, Jing Zhou, Edyta Marcon, Hongyue Ma, Xinyu Cui, Wuyue Chen, Haoyan Zhou, Yuan Gong, Bowen Zhu, Xiang Lv, Hongbo Guo, Jinao Duan, Jing Zhou, Edyta Marcon, Hongyue Ma

Abstract

COVID-19 mortality is primarily driven by abnormal alveolar fluid metabolism of the lung, leading to fluid accumulation in the alveolar airspace. 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. 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. 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. Among the currently pursued therapeutic strategies against COVID-19, little attention has been paid to abnormal lung humoral metabolism. 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.

Keywords: COVID-19; abnormal lung humoral metabolism; drug; pulmonary edema; syndrome coronavirus 2; traditional Chinese medicine.

Conflict of interest statement

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.

Copyright © 2021 Cui, Chen, Zhou, Gong, Zhu, Lv, Guo, Duan, Zhou, Marcon and Ma.

Figures

FIGURE 1
FIGURE 1
A vision of coronavirus with the minimal set of structural proteins.
FIGURE 2
FIGURE 2
Infection and replication process of SARS-CoV-2.
FIGURE 3
FIGURE 3
Cause of COVID-19 pulmonary edema.
FIGURE 4
FIGURE 4
Mechanism of inhibiting ENaC inducing pulmonary edema.
FIGURE 5
FIGURE 5
Mechanism of BK inducing pulmonary edema and potential drugs.
FIGURE 6
FIGURE 6
The general regulation approaches of AFC.

References

    1. Abdullah H., Heaney L. G., Cosby S. L., McGarvey L. P. A. (2014). Rhinovirus Upregulates Transient Receptor Potential Channels in a Human Neuronal Cell Line: Implications for Respiratory Virus-Induced Cough Reflex Sensitivity. Thorax 69 (1), 46–54. 10.1136/thoraxjnl-2013-203894
    1. Achanta S., Jordt S. E. (2020). Transient Receptor Potential Channels in Pulmonary Chemical Injuries and as Countermeasure Targets. Ann. N.Y. Acad. Sci. 1480 (1), 73–103. 10.1111/nyas.14472
    1. Adil M. S., Narayanan S. P., Somanath P. R. (2020). Is Amiloride a Promising Cardiovascular Medication to Persist in the COVID-19 Crisis?. DD&T 14 (5), 256–258. 10.5582/ddt.2020.03070
    1. Ahmed M. H., Hassan A. (2020). Dexamethasone for the Treatment of Coronavirus Disease (COVID-19): a Review. SN Compr. Clin. Med. 2, 2637–2646. 10.1007/s42399-020-00610-8
    1. Ai J.-W., Zhang H.-C., Xu T., Wu J., Zhu M., Yu Y.-Q., et al. (2020). Optimizing Diagnostic Strategy for Novel Coronavirus Pneumonia, a Multi-center Study in Eastern China. medRxiv. 10.1101/2020.02.13.20022673
    1. Alvarez D. F., King J. A., Weber D., Addison E., Liedtke W., Townsley M. I. (2006). Transient Receptor Potential Vanilloid 4-Mediated Disruption of the Alveolar Septal Barrier. Circ. Res. 99 (9), 988–995. 10.1161/01.RES.0000247065.11756.19
    1. Andrè E., Gatti R., Trevisani M., Preti D., Baraldi P., Patacchini R., et al. (2009). Transient Receptor Potential Ankyrin Receptor 1 Is a Novel Target for Pro-tussive Agents. Br. J. Pharmacol. 158 (6), 1621–1628. 10.1111/j.1476-5381.2009.00438.x
    1. Bailey A. L., Dmytrenko O., Greenberg L., Bredemeyer A. L., Ma P., Liu J., et al. (2021). SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis. JACC: Basic Translational Sci. 6, 331–345. 10.1016/j.jacbts.2021.01.002
    1. Bardou O., Privé A., Migneault F., Roy-Camille K., Dagenais A., Berthiaume Y., et al. (2012). K+ Channels Regulate ENaC Expression via Changes in Promoter Activity and Control Fluid Clearance in Alveolar Epithelial Cells. Biochim. Biophys. Acta (Bba) - Biomembranes 1818 (7), 1682–1690. 10.1016/j.bbamem.2012.02.025
    1. Bartoszewski R., Matalon S., Collawn J. F. (2017). Ion Channels of the Lung and Their Role in Disease Pathogenesis. Am. J. Physiology-Lung Cell Mol. Physiol. 313 (5), L859–L872. 10.1152/ajplung.00285.2017
    1. Beigel J. H., Tomashek K. M., Dodd L. E., Mehta A. K., Zingman B. S., Kalil A. C., et al. (2020). Remdesivir for the Treatment of Covid-19 - Final Report. N. Engl. J. Med. 383 (19), 1813–1826. 10.1056/NEJMoa2007764
    1. Bessac B. F., Jordt S.-E. (2008). Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control. Physiology 23, 360–370. 10.1152/physiol.00026.2008
    1. Birket S. E., Chu K. K., Houser G. H., Liu L., Fernandez C. M., Solomon G. M., et al. (2016). Combination Therapy with Cystic Fibrosis Transmembrane Conductance Regulator Modulators Augment the Airway Functional Microanatomy. Am. J. Physiology-Lung Cell Mol. Physiol. 310 (10), L928–L939. 10.1152/ajplung.00395.2015
    1. Birrell M. A., Belvisi M. G., Grace M., Sadofsky L., Faruqi S., Hele D. J., et al. (2009). TRPA1 Agonists Evoke Coughing in guinea Pig and Human Volunteers. Am. J. Respir. Crit. Care Med. 180 (11), 1042–1047. 10.1164/rccm.200905-0665OC
    1. Bull M. B., Laragh J. H. (1968). Amiloride. Circulation 37 (1), 45–53. 10.1161/01.cir.37.1.45
    1. Cai J., Li H., Zhang C., Chen Z., Liu H., Lei F., et al. (2021). The Neutrophil-To-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19. Cel Metab. 33, 258–269. 10.1016/j.cmet.2021.01.002
    1. Chen S.-y., Bhargava A., Mastroberardino L., Meijer O. C., Wang J., Buse P., et al. (1999). Epithelial Sodium Channel Regulated by Aldosterone-Induced Protein Sgk. Proc. Natl. Acad. Sci. 96 (5), 2514–2519. 10.1073/pnas.96.5.2514
    1. Chow Y.-H., Wang Y., Plumb J., O'Brodovich H., Hu J. (1999). Hormonal Regulation and Genomic Organization of the Human Amiloride-Sensitive Epithelial Sodium Channel α Subunit Gene. Pediatr. Res. 46 (2), 208–214. 10.1203/00006450-199908000-00014
    1. Christ-Crain M., Hoorn E. J., Sherlock M., Thompson C. J., Wass J. A. H. (2020). Endocrinology in the Time of COVID-19: Management of Diabetes Insipidus and Hyponatraemia. Eur. J. Endocrinol. 183 (1), G9–G15. 10.1530/EJE-20-0338
    1. Clapham D. E., Runnels L. W., Strübing C. (2001). The TRP Ion Channel Family. Nat. Rev. Neurosci. 2 (6), 387–396.10.1038/35077544
    1. Connors J. M., Levy J. H. (2020). COVID-19 and its Implications for Thrombosis and Anticoagulation. Blood 135 (23), 2033–2040. 10.1182/blood.2020006000
    1. Couto M., de Diego A., Perpiñi M., Delgado L., Moreira A. (2013). Cough Reflex Testing with Inhaled Capsaicin and TRPV1 Activation in Asthma and Comorbid Conditions. J. Investig. Allergol. Clin. Immunol. 23 (5), 289–301. 10.5114/pdia.2013.37040
    1. Cui M., Gosu V., Basith S., Hong S., Choi S. (2016). Polymodal Transient Receptor Potential Vanilloid Type 1 Nocisensor. Adv. Protein Chem. Struct. Biol. 104, 81–125. 10.1016/bs.apcsb.2015.11.005
    1. Cure E., Cumhur Cure M. (2020). Comment on "Organ‐protective Effect of Angiotensin‐converting Enzyme 2 and its Effect on the Prognosis of COVID‐19". J. Med. Virol. 92 (9), 1423–1424. 10.1002/jmv.25848
    1. Cutts S., Talboys R., Paspula C., Prempeh E., Fanous R., Ail D. (2017). Adult Respiratory Distress Syndrome. annals 99 (1), 12–16. 10.1308/rcsann.2016.0238
    1. de la Rosa D. A., Zhang P., Náray-Fejes-Tóth A., Fejes-Tóth G., Canessa C. M. (1999). The Serum and Glucocorticoid Kinase Sgk Increases the Abundance of Epithelial Sodium Channels in the Plasma Membrane of Xenopus Oocytes. J. Biol. Chem. 274 (53), 37834–37839. 10.1074/jbc.274.53.37834
    1. De Logu F., Patacchini R., Fontana G., Geppetti P. (2016). TRP Functions in the Broncho-Pulmonary System. Semin. Immunopathol 38 (3), 321–329. 10.1007/s00281-016-0557-1
    1. de Maat S., de Mast Q., Danser A. H. J., van de Veerdonk F. L., Maas C. (2020). Impaired Breakdown of Bradykinin and its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection. Semin. Thromb. Hemost. 46 (7), 835–837. 10.1055/s-0040-1712960
    1. Deng J., Wang D.-x., Deng W., Li C.-y., Tong J., Ma H. (2012). Regulation of Alveolar Fluid Clearance and ENaC Expression in Lung by Exogenous Angiotensin II. Respir. Physiol. Neurobiol. 181 (1), 53–61. 10.1016/j.resp.2011.11.009
    1. Fan H.-H., Wang L.-Q., Liu W.-L., An X.-P., Liu Z.-D., He X.-Q., et al. (2020). Repurposing of Clinically Approved Drugs for Treatment of Coronavirus Disease 2019 in a 2019-novel Coronavirus-Related Coronavirus Model. Chin. Med. J. (Engl) 133 (9), 1051–1056. 10.1097/CM9.0000000000000797
    1. Ferner R. E., Aronson J. K. (2020). Chloroquine and Hydroxychloroquine in Covid-19. BMJ 369, m1432. 10.1136/bmj.m1432
    1. Fleckenstein A. (1977). Specific Pharmacology of Calcium in Myocardium, Cardiac Pacemakers, and Vascular Smooth Muscle. Annu. Rev. Pharmacol. Toxicol. 17, 149–166. 10.1146/annurev.pa.17.040177.001053
    1. Fronius M. (2013). Treatment of Pulmonary Edema by ENaC Activators/Stimulators. Cmp 6 (1), 13–27. 10.2174/1874467211306010003
    1. Gabazza E. C., Kasper M., Ohta K., Keane M., D'Alessandro-Gabazza C., Fujimoto H., et al. (2004). Decreased Expression of Aquaporin-5 in Bleomycin-Induced Lung Fibrosis in the Mouse fibrosis in the Mouse. Pathol. Int. 54 (10), 774–780. 10.1111/j.1440-1827.2004.01754.x
    1. Garvin M. R., Alvarez C., Miller J. I., Prates E. T., Walker A. M., Amos B. K., et al. (2020). A Mechanistic Model and Therapeutic Interventions for COVID-19 Involving a RAS-Mediated Bradykinin Storm. Elife 9, e59177. 10.7554/eLife.59177
    1. George P. M., Wells A. U., Jenkins R. G. (2020). Pulmonary Fibrosis and COVID-19: the Potential Role for Antifibrotic Therapy. Lancet Respir. Med. 8 (8), 807–815. 10.1016/s2213-2600(20)30225-3
    1. Goldenberg N. M., Ravindran K., Kuebler W. M. (2015). TRPV4: Physiological Role and Therapeutic Potential in Respiratory Diseases. Naunyn-schmiedeberg's Arch. Pharmacol. 388 (4), 421–436. 10.1007/s00210-014-1058-1
    1. Grant R. A., Morales-Nebreda L., Morales-Nebreda L., Markov N. S., Swaminathan S., Querrey M., et al. (2021). Circuits between Infected Macrophages and T Cells in SARS-CoV-2 Pneumonia. Nature 590, 635–641. 10.1038/s41586-020-03148-w
    1. Guan W.-j., Ni Z.-y., Hu Y., Liang W.-h., Ou C.-q., He J.-x., et al. (2020). Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 382 (18), 1708–1720. 10.1056/NEJMoa2002032
    1. Guo Y.-R., Cao Q.-D., Hong Z.-S., Tan Y.-Y., Chen S.-D., Jin H.-J., et al. (2020). The Origin, Transmission and Clinical Therapies on Coronavirus Disease 2019 (COVID-19) Outbreak - an Update on the Status. Mil. Med Res 7 (1), 11. 10.1186/s40779-020-00240-0
    1. Han D.-Y., Nie H.-G., Gu X., Nayak R. C., Su X.-F., Fu J., et al. (2010). K+ Channel Openers Restore Verapamil-Inhibited Lung Fluid Resolution and Transepithelial Ion Transport. Respir. Res. 11 (1), 65. 10.1186/1465-9921-11-65
    1. Han J., Li H., Bhandari S., Cao F., Wang X. Y., Tian C., et al. (2020). Maresin Conjugates in Tissue Regeneration 1 Improves Alveolar Fluid Clearance by Up‐regulating Alveolar ENaC, Na, K‐ATPase in Lipopolysaccharide‐induced Acute Lung Injury. J. Cel Mol Med 24 (8), 4736–4747. 10.1111/jcmm.15146
    1. Harada H., Takahashi M. (2007). CD44-dependent Intracellular and Extracellular Catabolism of Hyaluronic Acid by Hyaluronidase-1 and -2. J. Biol. Chem. 282 (8), 5597–5607. 10.1074/jbc.M608358200
    1. Harmer D., Gilbert M., Borman R. (2002). Quantitative mRNA Expression Profiling of ACE 2, a Novel Homologue of Angiotensin Converting Enzyme. FEBS Lett. 532 (1), 4. 10.1016/s0014-5793(02)03640-2
    1. Heald-Sargent T., Gallagher T. (2012). Ready, Set, Fuse! the Coronavirus Spike Protein and Acquisition of Fusion Competence. Viruses 4 (4), 557–580. 10.3390/v4040557
    1. Ho T., Wu S., Chen J., Li C., Hsiang C. (2007). Emodin Blocks the SARS Coronavirus Spike Protein and Angiotensin-Converting Enzyme 2 Interaction. Antiviral Res. 74 (2), 92–101. 10.1016/j.antiviral.2006.04.014
    1. Hofer C. C., Woods P. S., Davis I. C. (2015). Infection of Mice with Influenza A/WSN/33 (H1N1) Virus Alters Alveolar Type II Cell Phenotype. Am. J. Physiology-Lung Cell Mol. Physiol. 308 (7), L628–L638. 10.1152/ajplung.00373.2014
    1. Hu F., Chen J., Chen H., Zhu J., Wang C., Ni H. B., et al. (2020). Chansu Injection Improves the Respiratory Function of Severe COVID-19 Patients. medRxiv.10.1101/2020.05.20.20107607
    1. Hu K., Guan W.-j., Bi Y., Zhang W., Li L., Zhang B., et al. (2021). Efficacy and Safety of Lianhuaqingwen Capsules, a Repurposed Chinese Herb, in Patients with Coronavirus Disease 2019: A Multicenter, Prospective, Randomized Controlled Trial. Phytomedicine 85, 153242. 10.1016/j.phymed.2020.153242
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. (2020). Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. The Lancet 395 (10223), 497–506. 10.1016/s0140-6736(20)30183-5
    1. Hui D. S. C., Zumla A. (2019). Severe Acute Respiratory Syndrome. Infect. Dis. Clin. North America 33 (4), 869–889. 10.1016/j.idc.2019.07.001
    1. Imai Y., Kuba K., Penninger J. M. (2007). Angiotensin-converting Enzyme 2 in Acute Respiratory Distress Syndrome. Cell. Mol. Life Sci. 64 (15), 2006–2012. 10.1007/s00018-007-6228-6
    1. Itani O. A., Auerbach S. D., Husted R. F., Volk K. A., Ageloff S., Knepper M. A., et al. (2001). Glucocorticoid-stimulated Lung Epithelial Na(+) Transport Is Associated with Regulated ENaC and Sgk1 Expression. Am. J. Physiol. Lung Cel Mol Physiol 282, L631–L641. 10.1152/ajplung.00085.2001
    1. Ito Y., Correll K., Zemans R. L., Leslie C. C., Murphy R. C., Mason R. J. (2015). Influenza Induces IL-8 and GM-CSF Secretion by Human Alveolar Epithelial Cells through HGF/c-Met and TGF-α/EGFR Signaling. Am. J. Physiology-Lung Cell Mol. Physiol. 308 (11), L1178–L1188. 10.1152/ajplung.00290.2014
    1. Ji G., Chen R., Zheng J. (2014). Atractylenolide I Inhibits Lipopolysaccharide-Induced Inflammatory Responses via Mitogen-Activated Protein Kinase Pathways in RAW264.7 Cells. Immunopharmacology and Immunotoxicology 36 (6), 420–425. 10.3109/08923973.2014.968256
    1. Jiang Y.-x., Dai Z.-l., Zhang X.-p., Zhao W., Huang Q., Gao L.-k. (2015). Dexmedetomidine Alleviates Pulmonary Edema by Upregulating AQP1 and AQP5 Expression in Rats with Acute Lung Injury Induced by Lipopolysaccharide. J. Huazhong Univ. Sci. Technol. [Med. Sci. 35 (5), 684–688. 10.1007/s11596-015-1490-6
    1. Jovanović S., Crawford R. M., Ranki H. J., Jovanović A. (2003). Large Conductance Ca2+-Activated K+ Channels Sense Acute Changes in Oxygen Tension in Alveolar Epithelial Cells. Am. J. Respir. Cel Mol Biol 28 (3), 363–372. 10.1165/rcmb.2002-0101OC
    1. Kaneko Y., Szallasi A. (2014). Transient Receptor Potential (TRP) Channels: a Clinical Perspective. Br. J. Pharmacol. 171 (10), 2474–2507. 10.1111/bph.12414
    1. Kaur S. P., Gupta V. (2020). COVID-19 Vaccine: A Comprehensive Status Report. Virus. Res. 288, 198114. 10.1016/j.virusres.2020.198114
    1. Królicka A. L., Kruczkowska A., Krajewska M., Kusztal M. A. (2020). Hyponatremia in Infectious Diseases-A Literature Review. Ijerph 17 (15), 5320. 10.3390/ijerph17155320
    1. Kunzelmann K., Beesley A. H., King N. J., Karupiah G., Young J. A., Cook D. I. (2000). Influenza Virus Inhibits Amiloride-Sensitive Na+ Channels in Respiratory Epithelia. Proc. Natl. Acad. Sci. 97 (18), 10282–10287. 10.1073/pnas.160041997
    1. Leroy C., Privé A., Bourret J.-C., Berthiaume Y., Ferraro P., Brochiero E. (2006). Regulation of ENaC and CFTR Expression with K+ Channel Modulators and Effect on Fluid Absorption across Alveolar Epithelial Cells. Am. J. Physiology-Lung Cell Mol. Physiol. 291 (6), L1207–L1219. 10.1152/ajplung.00376.2005
    1. Li C., Wang P., Li M., Zheng R., Chen S., Liu S., et al. (2021). The Current Evidence for the Treatment of Sepsis with Xuebijing Injection: Bioactive Constituents, Findings of Clinical Studies and Potential Mechanisms. J. Ethnopharmacology 265, 113301. 10.1016/j.jep.2020.113301
    1. Li F. (2016). Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol. 3 (1), 237–261. 10.1146/annurev-virology-110615-042301
    1. Li L., Zhang W., Hu Y., Tong X., Zheng S., Yang J., et al. (2020). Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-Threatening COVID-19. JAMA 324 (5), 460–470. 10.1001/jama.2020.10044
    1. Lippi G., South A. M., Henry B. M. (2020). Electrolyte Imbalances in Patients with Severe Coronavirus Disease 2019 (COVID-19). Ann. Clin. Biochem. 57 (3), 262–265. 10.1177/0004563220922255
    1. Liu Y., Huang F., Xu J., Yang P., Qin Y., Cao M., et al. (2020). Anti-hypertensive Angiotensin II Receptor Blockers Associated to Mitigation of Disease Severity in Elderly COVID-19 Patients. medRxiv. 10.1101/2020.03.20.20039586
    1. Londino J. D., Lazrak A., Collawn J. F., Bebok Z., Harrod K. S., Matalon S. (2017). Influenza Virus Infection Alters Ion Channel Function of Airway and Alveolar Cells: Mechanisms and Physiological Sequelae. Am. J. Physiology-Lung Cell Mol. Physiol. 313 (5), L845–L858. 10.1152/ajplung.00244.2017
    1. Looney M. R., Sartori C., Chakraborty S., James P. F., Lingrel J. B., Matthay M. A. (2005). Decreased Expression of Both the α1- and α2-subunits of the Na-K-ATPase Reduces Maximal Alveolar Epithelial Fluid Clearance. Am. J. Physiology-Lung Cell Mol. Physiol. 289 (1), L104–L110. 10.1152/ajplung.00464.2004
    1. Lung J., Lin Y. S., Yang Y. H., Chou Y. L., Shu L. H., Cheng Y. C., et al. (2020). The Potential Chemical Structure of anti‐SARS‐CoV‐2 RNA‐dependent RNA Polymerase. J. Med. Virol. 92 (6), 693–697. 10.1002/jmv.25761
    1. Luo X., Ni X., Lin J., Zhang Y., Wu L., Huang D., et al. (2021). The Add-On Effect of Chinese Herbal Medicine on COVID-19: A Systematic Review and Meta-Analysis. Phytomedicine 85, 153282. 10.1016/j.phymed.2020.153282
    1. Ma Q., Pan W., Li R., Liu B., Li C., Xie Y., et al. (2020a). Liu Shen Capsule Shows Antiviral and Anti-inflammatory Abilities against Novel Coronavirus SARS-CoV-2 via Suppression of NF-Κb Signaling Pathway. Pharmacol. Res. 158, 104850. 10.1016/j.phrs.2020.104850
    1. Ma Q., Qiu M., Zhou H., Chen J., Yang X., Deng Z., et al. (2020b). The Study on the Treatment of Xuebijing Injection (XBJ) in Adults with Severe or Critical Corona Virus Disease 2019 and the Inhibitory Effect of XBJ against SARS-CoV-2. Pharmacol. Res. 160, 105073. 10.1016/j.phrs.2020.105073
    1. Maronde R. F., Milgrom M., Vlachakis N. D., Chan L. (1983). Response of Thiazide-Induced Hypokalemia to Amiloride. JAMA 249 (2), 237–241. 10.1001/jama.249.2.237
    1. Matalon S. (1999). SODIUM CHANNELS IN ALVEOLAR EPITHELIAL CELLS: Molecular Characterization, Biophysical Properties, and Physiological Significance. Annu. Rev. Physiol. 61, 35. 10.1146/annurev.physiol.61.1.627
    1. Matthay M. A., Clerici C., Saumon G. (2002). Invited Review: Active Fluid Clearance from the Distal Air Spaces of the Lung. J. Appl. Physiol.(1985) 93 (4), 1533–1541. 10.1152/japplphysiol.01210.2001
    1. McCreary E. K., Pogue J. M. (2020). Coronavirus Disease 2019 Treatment A Review of Early and Emerging Options. Open Forum Infect. Dis. 7 (4). 10.1093/ofid/ofaa105/5811022
    1. Minakata Y., Suzuki S., Grygorczyk C., Dagenais A., Berthiaume Y. (1998). Impact of β-adrenergic Agonist on Na+ Channel and Na+-K+-ATPase Expression in Alveolar Type II Cells. Am. J. Physiology-Lung Cell Mol. Physiol. 275 (2), L414–L422. 10.1152/ajplung.1998.275.2.L414
    1. Mutlu G. M., Dumasius V., Burhop J., McShane P. J., Meng F. J., Welch L., et al. (2004). Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on β 2 -Adrenergic Receptor Signaling. Circ. Res. 94 (8), 1091–1100. 10.1161/01.RES.0000125623.56442.20
    1. Nayler W., Dillon J. (1986). Calcium Antagonists and Their Mode of Action: an Historical Overview. Br. J. Clin. Pharmacol. 21, 97S–107S. 10.1111/j.1365-2125.1986.tb02859.x
    1. Negrini D., Passi A., de Luca G., Miserocchi G. (1998). Proteoglycan Involvement during Development of Lesional Pulmonary Edema. Am. J. Physiology-Lung Cell Mol. Physiol. 274, L203–L211. 10.1152/ajplung.1998.274.2.l203
    1. Negrini D., Passi A., de Luca G., Miserocchi G. (1996). Pulmonary Interstitial Pressure and Proteoglycans during Development of Pulmonary Edema. Am. J. Physiol. Heart Circ. Physiol. 39 (270), H2000–H2007. 10.1152/ajpheart.1996.270.6.h2000
    1. Negrini D., Passi A., Moriondo A. (2008). The Role of Proteoglycans in Pulmonaryedema Development. Intensive Care Med. 34 (4), 610–618. 10.1007/s00134-007-0962-y
    1. Niu F., Xu X., Zhang R., Sun L., Gan N., Wang A. (2019). Ursodeoxycholic Acid Stimulates Alveolar Fluid Clearance in LPS‐induced Pulmonary Edema via ALX/cAMP/PI3K Pathway. J. Cel Physiol 234 (11), 20057–20065. 10.1002/jcp.28602
    1. Otulakowski G., Rafii B., Bremner H. R., O'Brodovich H. (1999). Structure and Hormone Responsiveness of the Gene Encoding the α -Subunit of the Rat Amiloride-Sensitive Epithelial Sodium Channel. Am. J. Respir. Cel Mol Biol 20 (5), 1028–1040. 10.1165/ajrcmb.20.5.3382
    1. Pascarella G., Strumia A., Piliego C., Bruno F., Del Buono R., Costa F., et al. (2020). COVID‐19 Diagnosis and Management: a Comprehensive Review. J. Intern. Med. 288 (2), 192–206. 10.1111/joim.13091
    1. Passi A., Negrini D., Albertini R., de Luca G., Miserocchi G. (1998). Involvement of Lung Interstitial Proteoglycans in Development of Hydraulic- and Elastase-Induced Edema. Am. J. Physiology-Lung Cell Mol. Physiol. 275(3), L631–L635. 10.1152/ajplung.1998.275.3.L631
    1. Perkins G. D., McAuley D. F., Thickett D. R., Gao F. (2006). The β-Agonist Lung Injury Trial (Balti). Am. J. Respir. Crit. Care Med. 173 (3), 281–287. 10.1164/rccm.200508-1302OC
    1. Pickkers P., Dormans T. P. J., Russel F. G. M., Hughes A. D., Thien T., Schaper N., et al. (1997). Direct Vascular Effects of Furosemide in Humans. Circulation 96 (6), 1847–1852. 10.1161/01.cir.96.6.1847
    1. Prc N. H. C. o. t. (2020). COVID-19 Treatment and Diagnosis Guideline (7th version, trial) [Online]. Available: (Accessed February 4, 2021).
    1. Qu G. J. (2019). Effect and Mechanism of Astragaloside A on Acute Respiratory Failure in Rats. J. Pract. Med. 35 (19), 3014–2017. 10.3969/j.issn.1006⁃5725.2019.19.008
    1. Rasaeifar B., Gomez-Gutierrez P., Perez J. J. (2020). Molecular Features of Non-selective Small Molecule Antagonists of the Bradykinin Receptors. Pharmaceuticals 13 (9), 259. 10.3390/ph13090259
    1. Ren J.-l., Zhang A.-H., Wang X.-J. (2020). Traditional Chinese Medicine for COVID-19 Treatment. Pharmacol. Res. 155, 104743. 10.1016/j.phrs.2020.104743
    1. Richardson S., Hirsch J. S., Narasimhan M., Crawford J. M., McGinn T., Davidson K. W., et al. (2020). Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized with COVID-19 in the New York City Area. JAMA 323 (20), 2052–2059. 10.1001/jama.2020.6775
    1. Rogosnitzky M., Okediji P., Koman I. (2020). Cepharanthine: a Review of the Antiviral Potential of a Japanese-approved Alopecia Drug in COVID-19. Pharmacol. Rep. 72 (6), 1509–1516. 10.1007/s43440-020-00132-z
    1. Runfeng L., Yunlong H., Jicheng H., Weiqi P., Qinhai M., Yongxia S., et al. (2020). Lianhuaqingwen Exerts Anti-viral and Anti-inflammatory Activity against Novel Coronavirus (SARS-CoV-2). Pharmacol. Res. 156, 104761. 10.1016/j.phrs.2020.104761
    1. Sartori C., Allemann Y., Duplain H., Lepori M., Egli M., Lipp E., et al. (2002). Salmeterol for the Prevention of High-Altitude Pulmonary Edema. N. Engl. J. Med. 346, 1631–1636. 10.1056/NEJMoa013183
    1. Sayegh R., Auerbach S. D., Li X., Loftus R. W., Husted R. F., Stokes J. B., et al. (1999). 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 α Subunit Gene. J. Biol. Chem. 274 (18), 12431–12437. 10.1074/jbc.274.18.12431
    1. Schlagenhauf P., Grobusch M. P., Maier J. D., Gautret P. (2020). Repurposing Antimalarials and Other Drugs for COVID-19. Trav. Med. Infect. Dis. 34, 101658. 10.1016/j.tmaid.2020.101658
    1. Shapiro S. D. (2001). Matrix Proteinases in Lung Biology. Respir. Res. 2, 10–19.
    1. Sharma A., Garcia G., Jr., Wang Y., Plummer J. T., Morizono K., Arumugaswami V., et al. (2020). Human iPSC-Derived Cardiomyocytes Are Susceptible to SARS-CoV-2 Infection. Cel Rep. Med. 1 (4), 100052. 10.1016/j.xcrm.2020.100052
    1. Shen C., Wang Z., Zhao F., Yang Y., Li J., Yuan J., et al. (2020). Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma. JAMA 323 (16), 1582–1589. 10.1001/jama.2020.4783
    1. Shi N., Liu B., Liang N., Ma Y., Ge Y., Yi H., et al. (2020a). Association between Early Treatment with Qingfei Paidu Decoction and Favorable Clinical Outcomes in Patients with COVID-19: A Retrospective Multicenter Cohort Study. Pharmacol. Res. 161, 105290. 10.1016/j.phrs.2020.105290
    1. Shi Y., Wang Y., Shao C., Huang J., Gan J., Huang X., et al. (2020b). COVID-19 Infection: the Perspectives on Immune Responses. Cell Death Differ 27 (5), 1451–1454. 10.1038/s41418-020-0530-3
    1. Shi Z., Ye W., Zhang J., Zhang F., Yu D., Yu H., et al. (2018). 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. Mol. Immunol. 103, 78–88. 10.1016/j.molimm.2018.09.003
    1. Solymosi E. A., Kaestle-Gembardt S. M., Vadasz I., Wang L., Neye N., Chupin C. J. A., et al. (2013). Chloride Transport-Driven Alveolar Fluid Secretion Is a Major Contributor to Cardiogenic Lung Edema. Proc. Natl. Acad. Sci. 110 (25), E2308–E2316. 10.1073/pnas.1216382110
    1. Staub N. C. (1974). Pulmonary Edema. Physiol. Rev. 54 (3), 678–811. 10.1152/physrev.1974.54.3.678
    1. Steinritz D., Stenger B., Dietrich A., Gudermann T., Popp T. (2018). TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity-A Structured Review. Cells 7 (8), 98. 10.3390/cells7080098
    1. Stone J. H., Frigault M. J., Serling-Boyd N. J., Fernandes A. D., Harvey L., Foulkes A. S., et al. (2020). Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N. Engl. J. Med. 383, 2333–2344. 10.1056/NEJMoa2028836
    1. Tang Y., Liu J., Zhang D., Xu Z., Ji J., Wen C. (2020). Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Front. Immunol. 11, 1708. 10.3389/fimmu.2020.01708
    1. Thanh Le T., Andreadakis Z., Kumar A., Gómez Román R., Tollefsen S., Saville M., et al. (2020). The COVID-19 Vaccine Development Landscape. Nat. Rev. Drug Discov. 19 (5), 305–306. 10.1038/d41573-020-00073-5
    1. Thorneloe K. S., Cheung M., Bao W., Alsaid H., Lenhard S., Jian M.-Y., et al. (2012). An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure. Sci. Transl. Med. 4 (159), 159ra148. 10.1126/scitranslmed.3004276
    1. Towne J. E., Krane C. M., Bachurski C. J., Menon A. G. (2001). Tumor Necrosis Factor-α Inhibits Aquaporin 5 Expression in Mouse Lung Epithelial Cells. J. Biol. Chem. 276 (22), 18657–18664. 10.1074/jbc.M100322200
    1. Udugama B., Kadhiresan P., Kozlowski H. N., Malekjahani A., Osborne M., Li V. Y. C., et al. (2020). Diagnosing COVID-19: The Disease and Tools for Detection. ACS Nano 14 (4), 3822–3835. 10.1021/acsnano.0c02624
    1. Walls A. C., Park Y.-J., Tortorici M. A., Wall A., McGuire A. T., Veesler D. (2020). Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 181 (2), 281–292. 10.1016/j.cell.2020.02.058
    1. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., et al. (2020). Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 323 (11), 1061–1069. 10.1001/jama.2020.1585
    1. Wang Q. Y., Liang W., Jiang C., Li N. Y., Xu H., Yang M. N., et al. (2015). [Effect of Astragali Radix in Improving Early Renal Damage in Metabolic Syndrome Rats through ACE2/Mas Pathway]. Zhongguo Zhong Yao Za Zhi 40 (21), 4245–4250. 10.4268/cjcmm20152124
    1. Wang Q., Zheng X., Cheng Y., Zhang Y.-L., Wen H.-X., Tao Z., et al. (2014). 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. J.I. 192 (8), 3765–3777. 10.4049/jimmunol.1302421
    1. Who (2021). WHO Coronavirus Disease (COVID-19) Dashboard [Online]. Available: (Accessed March 31, 2021).
    1. Wiersinga W. J., Rhodes A., Cheng A. C., Peacock S. J., Prescott H. C. (2020). Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19). JAMA 324 (8), 782–793. 10.1001/jama.2020.12839
    1. Wittekindt O. H., Dietl P. (2019). Aquaporins in the Lung. Pflugers Arch. - Eur. J. Physiol. 471 (4), 519–532. 10.1007/s00424-018-2232-y
    1. Woods P. S., Tazi M. F., Chesarino N. M., Amer A. O., Davis I. C. (2015). TGF-β-induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. Am. J. Physiology-Lung Cell Mol. Physiol. 308 (11), L1136–L1144. 10.1152/ajplung.00078.2015
    1. Wösten-van Asperen R. M., Lutter R., Specht P. A., Moll G. N., van Woensel J. B., van der Loos C. M., et al. (2011). 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. Pathol. 225 (4), 618–627. 10.1002/path.2987
    1. Wrapp D., Wang N., Corbett K. S., Goldsmith J. A., Hsieh C.-L., Abiona O., et al. (2020). Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. Science 367 (6483), 1260–1263. 10.1126/science.abb2507
    1. Xu X., Chen P., Wang J., Feng J., Zhou H., Li X., et al. (2020a). Evolution of the Novel Coronavirus from the Ongoing Wuhan Outbreak and Modeling of its Spike Protein for Risk of Human Transmission. Sci. China Life Sci. 63 (3), 457–460. 10.1007/s11427-020-1637-5
    1. Xu Y.-H., Dong J.-H., An W.-M., Lv X.-Y., Yin X.-P., Zhang J.-Z., et al. (2020b). Clinical and Computed Tomographic Imaging Features of Novel Coronavirus Pneumonia Caused by SARS-CoV-2. J. Infect. 80 (4), 394–400. 10.1016/j.jinf.2020.02.017
    1. Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., et al. (2020c). Pathological Findings of COVID-19 Associated with Acute Respiratory Distress Syndrome. Lancet Respir. Med. 8 (4), 420–422. 10.1016/s2213-2600(20)30076-x
    1. Yan H., Valdes A. M., Vijay A., Wang S., Liang L., Yang S., et al. (2020a). Role of Drugs Used for Chronic Disease Management on Susceptibility and Severity of COVID‐19: A Large Case‐Control Study. Clin. Pharmacol. Ther. 108 (6), 1185–1194. 10.1101/2020.04.24.2007787510.1002/cpt.2047
    1. Yan R., Zhang Y., Li Y., Xia L., Guo Y., Zhou Q. (2020b). Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human ACE2. Science 367 (6485), 1444–1448. 10.1126/science.abb2762
    1. Yang G., Tan Z., Zhou L., Yang M., Peng L., Liu J., et al. (2020a). 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. medRxiv. 10.1101/2020.03.31.20038935
    1. Yang R., Liu H., Bai C., Wang Y., Zhang X., Guo R., et al. (2020b). 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. Pharmacol. Res. 157, 104820. 10.1016/j.phrs.2020.104820
    1. Yang X., Yu Y., Xu J., Shu H., Xia J. a., Liu H., et al. (2020c). Clinical Course and Outcomes of Critically Ill Patients with SARS-CoV-2 Pneumonia in Wuhan, China: a Single-Centered, Retrospective, Observational Study. Lancet Respir. Med. 8 (5), 475–481. 10.1016/s2213-2600(20)30079-5
    1. Yang Y., Islam M. S., Wang J., Li Y., Chen X. (2020d). Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A Review and Perspective. Int. J. Biol. Sci. 16 (10), 1708–1717. 10.7150/ijbs.45538
    1. Yang Y., Shen C., Li J., Yuan J., Yang M., Wang F., et al. (2020e). Exuberant Elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 Infection Is Associated with Disease Severity and Fatal Outcome. medRxiv. 10.1101/2020.03.02.20029975
    1. Yin J., Hoffmann J., Kaestle S. M., Neye N., Wang L., Baeurle J., et al. (2008). Negative-feedback Loop Attenuates Hydrostatic Lung Edema via a cGMP-dependent Regulation of Transient Receptor Potential Vanilloid 4. Circ. Res. 102 (8), 966–974. 10.1161/CIRCRESAHA.107.168724
    1. Yin J., Michalick L., Tang C., Tabuchi A., Goldenberg N., Dan Q., et al. (2016). Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury. Am. J. Respir. Cel Mol Biol 54 (3), 370–383. 10.1165/rcmb.2014-0225OC
    1. Yu Q., Wang D., Wen X., Tang X., Qi D., He J., et al. (2020). Adipose-derived Exosomes Protect the Pulmonary Endothelial Barrier in Ventilator-Induced Lung Injury by Inhibiting the TRPV4/Ca2+ Signaling Pathway. Am. J. Physiology-Lung Cell Mol. Physiol. 318 (4), L723–L741. 10.1152/ajplung.00255.2019
    1. Zhang B.-M., Wang Z.-B., Xin P., Wang Q.-H., Bu H., Kuang H.-X. (2018). Phytochemistry and Pharmacology of Genus Ephedra. Chin. J. Nat. Medicines 16 (11), 811–828. 10.1016/s1875-5364(18)30123-7
    1. Zhang D., Zhang B., Lv J.-T., Sa R.-N., Zhang X.-M., Lin Z.-J. (2020a). The Clinical Benefits of Chinese Patent Medicines against COVID-19 Based on Current Evidence. Pharmacol. Res. 157, 104882. 10.1016/j.phrs.2020.104882
    1. Zhang H., Baker A. (2017). Recombinant Human ACE2: Acing Out Angiotensin II in ARDS Therapy. Crit. Care 21 (1), 305. 10.1186/s13054-017-1882-z
    1. Zhang H., Kang Z., Gong H., Xu D., Wang J., Li Z., et al. (2020b). Digestive System Is a Potential Route of COVID-19: an Analysis of Single-Cell Coexpression Pattern of Key Proteins in Viral Entry Process. Gut 69 (6), 1010–1018. 10.1136/gutjnl-2020-320953
    1. Zhang J.-L., Zhuo X.-J., Lin J., Luo L.-C., Ying W.-Y., Xie X., et al. (2017). Maresin1 Stimulates Alveolar Fluid Clearance through the Alveolar Epithelial Sodium Channel Na,K-ATPase via the ALX/PI3K/Nedd4-2 Pathway. Lab. Invest. 97 (5), 543–554. 10.1038/labinvest.2016.150
    1. Zhang P. h., Han J., Cao F., Liu Y. j., Tian C., Wu C. h., et al. (2020c). PCTR1 Improves Pulmonary Edema Fluid Clearance through Activating the Sodium Channel and Lymphatic Drainage in Lipopolysaccharide‐induced ARDS. J. Cel Physiol 235 (12), 9510–9523. 10.1002/jcp.29758
    1. Zhang W., Xia X., Reisenauer M. R., Rieg T., Lang F., Kuhl D., et al. (2007). Aldosterone-induced Sgk1 Relieves Dot1a-Af9-Mediated Transcriptional Repression of Epithelial Na+ Channel α. J. Clin. Invest. 117 (3), 773–783. 10.1172/JCI29850
    1. Zhao J., Tian S., Lu D., Yang J., Zeng H., Zhang F., et al. (2021). Systems Pharmacological Study Illustrates the Immune Regulation, Anti-infection, Anti-inflammation, and Multi-Organ protection Mechanism of Qing-Fei-Pai-Du Decoction in the Treatment of COVID-19. Phytomedicine 85, 153315. 10.1016/j.phymed.2020.153315
    1. Zhou Z., Wang S.-Q., Liu Y., Miao A.-D. (2006). Cryptotanshinone Inhibits Endothelin-1 Expression and Stimulates Nitric Oxide Production in Human Vascular Endothelial Cells. Biochim. Biophys. Acta (Bba) - Gen. Subjects 1760 (1), 1–9. 10.1016/j.bbagen.2005.09.009
    1. Zhuo X.-J., Hao Y., Cao F., Yan S.-F., Li H., Wang Q., et al. (2018). Protectin DX Increases Alveolar Fluid Clearance in Rats with Lipopolysaccharide-Induced Acute Lung Injury. Exp. Mol. Med. 50 (4), 1–13. 10.1038/s12276-018-0075-4
    1. Zwaveling S., Gerth van Wijk R., Karim F. (2020). Pulmonary Edema in COVID-19: Explained by Bradykinin?. J. Allergy Clin. Immunol. 146 (6), 1454–1455. 10.1016/j.jaci.2020.08.038

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever