Publique un comentario 
Ácidos biliares y pulmón: expectativas a tener en cuenta en la COVID-19
Texto completo:
PDFResumen
Ácidos biliares, moléculas de señalización, mantienen la tolerancia inmunitaria, su descontrol amplifica la respuesta inflamatoria desde el sistema hepato-intestinal hacia otros órganos como pulmón. La disfunción hepática afecta estructuras anatomofuncionales de varios órganos e incrementa el riesgo de mortalidad por la citotoxicidad de los ácidos biliares. Para describir las posibles evidencias biomoleculares que pudieran respaldar a los ácidos biliares agentes proinflamatorios de las complicaciones respiratorias en la Covid-19, se presenta una revisión sistemática y crítica de lo publicado entre 1946-2021, sobre las acciones toxicas de los ácidos biliares en condiciones suprafisiológicas sobre el tejido alveolar. Esto pudieran constituir el fundamento teórico que asocia la disfunción hepato-intestinal-ácidos biliares- daño alveolar en la COVID-19, y permitiría la hipótesis de considerar los ácidos biliares constituyentes de un eje que transversaliza el proceso de la COVID-19, al participar activamente en sus estadios clínicos, y por ende ser agentes metabolomicos que amplifican o perpetúan la respuesta inflamatoria creada por el SARS-CoV2. Se recomienda estudios clínicos para su confirmación en el progreso del síndrome de dificultad respiratoria aguda.
Palabras clave
Referencias
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. [Internet]. 2020. [Consultado 2021 ene 22];395(10229):1054e62. Disponible en: https://doi.org/10.1016/S0140-6736(20)30566-3.
Chu H, Chan JF, Wang Y, Yuen TT, Chai Y, Hou Y, et al. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19.Clin Infect Dis. [Internet]. 2020 [Consultado 2021 ene 22];71(6):1400–09. Disponible en: https://doi.org/10.1093/cid/ciaa410.
Carsana L, Sonzogni A, Nasr A, Rossi R, Pellegrinelli A, Zerbi P, et al. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. Med Rxiv. [Internet]. 2020. [Consultado 2021 ene 22];04.19.20054262. Disponible en: https://doi.org/10.1101/2020.04.19.20054262.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. [Internet]. 2020. [Consultado 2021 ene 22];395:507–13. Disponible en: https://doi.org/10.1016/S1473-3099(20)30434-5
Feng G, Zheng K, Yan Q, Rios R, Targher G, Byrne C, Poucke S, et al. COVID-19 and Liver Dysfunction: Current Insights and Emergent Therapeutic Strategies. J Clin Trans Hepato. [Internet]. 2020. [Consultado 2021 ene 22];8(1):18-24. Disponible en: https://doi.org/10.14218/JCTH.2020.00018.
Fiorucci S, Biagioli M, Zampella A, Distrutti E. Bile acids activated receptors regulate innate immunity. Front Immunol. [Internet].2018. [Consultado 2021 ene 22];9:1853. Disponible en: https://doi.org/10.3389/fimmu.2018.01853.
Aldhahrani A, Verdon B, Ward C, Pearson J. Effects of bile acids on human airway epithelial cells: implications for aerodigestive diseases. ERJ Open Res. [Internet]. 2017. [Consultado 2021 ene 22];3:00107-2016. Disponible en: https://doi.org/10.1183/23120541.00107-2016
Perez MJ, Briz O. Bile-acid-induced cell injury and protection. W J Gastroenterol. [Internet].2009. [Consultado 2021 ene 22];15(14):1677-89. Disponible en: http://dx.doi.org/10.3748/wjg.15.1677.
Wu JN, Chen JR, Chen JL. Role of Farnesoid X Receptor in the Pathogenesis of Respiratory Diseases. Can Respir J. [Internet]. 2020 [Consultado 2021 ene 22];2020:9137251. Disponible en: https://doi.org/10.1155/2020/9137251.
Raftery AL, Tsantikos E, Harris NL, Hibbs ML. Links between inflammatory bowel disease and chronic obstructive pulmonary disease. Front Immunol. [Internet]. 2020. [Consultado 2021 ene 22];11:2144. Disponible en: https://doi.org/10.3389/fimmu.2020.02144.
Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. [Internet]. 1999. [Consultado 2021 ene 22];159(22):2647-58. Disponible en: https://doi.org/10.1001/archinte.159.22.2647.
Lee J, Im JP, Han K, Park S, Soh H, Choi K, et al. Risk of inflammatory bowel disease in patients with chronic obstructive pulmonary disease: a nationwide, population-based study. World J Gastroenterol. [Internet]. 2019. [Consultado 2021 ene 22];25:6354–64. Disponible en: https://doi.org/10.3748/wjg.v25.i42.6354.
Krones E, Wagner M, Eller K, Rosenkranz AR, Trauner M, Fickert P. Bile Acid-Induced Cholemic Nephropathy. Dig Dis. [Internet]. 2015. [Consultado 2021 ene 22];33:367–75. Disponible en: https://doi.org/10.1159/000371689.
Zecca E, De Luca D, Baroni S, Vento G, Tiberi E, Romagnoli C. Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study. Pediatrics. [Internet]. 2008. [Consultado 2021 ene 22];121:e146–e9. Disponible en: https://doi.org/10.1542/peds.2007-1220.
Desai M, Mathur B, Eblimit Z, Vasquez H, Taegtmeyer H, Karpen S, et al. Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology. [Internet]. 2017. [Consultado 2021 ene 22];65(1):189–201. Disponible en: https://doi.org/10.1002/hep.28890.
Chan S, Spraggon ES, Francis L, Wolley MJ. Bile cast nephropathy in a patient with obstructive jaundice. Kidney Int Rep. [Internet]. 2019. [Consultado 2021 ene 22];4,338–40. Disponible en: https://doi.org/10.1016/j.ekir.2018.09.008.
Zhao C, Wang X, Cong Y, Deng Y, Xu Y, et al. Effects of Bile Acids and the Bile Acid Receptor FXR Agonist on the Respiratory Rhythm in the In Vitro Brainstem Medulla Slice of Neonatal Sprague-Dawley Rats. PLoS ONE. [Internet]. 2014. [Consultado 2021 ene 22];9(11):e112212. Disponible en: http://doi.org/:10.1371/journal.pone.0112212.
Kiriyama Y, Nochi H. The biosynthesis, signaling, and neurological functions of bile acids. Biomolecules. [Internet]. 2019. [Consultado 2021 ene 22];9,232. Disponible en: http://doi.org/:10.3390/biom9060232
Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. [Internet]. 2010. [Consultado 2021 ene 22];363: 1128–38. Disponible en: http://doi.org/:10.1056/NEJMoa0909883.
Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. [Internet]. 2001 [Consultado 2021 ene 22];344: 665–71. Disponible en: http://doi.org/:10.1056/NEJM200103013440908.
Guillot L, Nathan N, Tabary O, Thouvenin G, Le Rouzic P, Corvol H, Amselem S, Clement A. Alveolar epithelial cells: master regulators of lung homeostasis. Int J Biochem Cell Biol. [Internet]. 2013 [Consultado 2021 ene 22];45(11):2568-73. Disponible en: https://doi.org/10.1016/j.biocel.2013.08.009.
Lugones Y, Blanco O, López-Rodriguez E, Echaide M, Cruz A, Pérez-Gil J. Inhibition and counterinhibition of Surfacen, a clinical lung surfactant of natural origin. PLoS ONE. [Internet]. 2018. [Consultado 2021 ene 22];13(9):e0204050. Disponible en: https://doi.org/10.1371/journal.pone.0204050.
Sardesai S, Biniwale M, Wertheimer F, Garingo A, Ramanathan R. Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future. Pediatr Res. [Internet]. 2017. [Consultado 2021 ene 22];81(1-2):240-8. Disponible en: https://doi.org/10.1038/pr.2016.203.
Nkadi PO, Merritt TA, Pillers DAM. An overview of pulmonary surfactant in the neonate: genetics, metabolism, and the role of surfactant in health and disease. Mol Genet Metab. [Internet]. 2009. [Consultado 2021 ene 22];97:95–101. Disponible en: https://doi.org/10.1016/j.ymgme.2009.01.015.
Sorensen GL. Surfactant protein D in respiratory and Non-respiratory diseases. Front Med. [Internet]. 2018. [Consultado 2021 ene 22];5:18. Disponible en: https://doi.org/10.3389/fmed.2018.00018
Hughes DA, Haslam PL. Effect of smoking on the lipid composition of lung lining fluid and relationship between immunostimulatory lipids, inflammatory cells and foamy macrophages in extrinsic allergic alveolitis. Eur Respir J. [Internet]. 1990. [Consultado 2021 ene 22];3:1128–39. Disponible en: https://pubmed.ncbi.nlm.nih.gov/2090475/.
Wang F, Zhao C, Tian YH, Yin YR. Effect of high blood levels of bile acid on respiratory functions of New Zealand rabbits. J South Med Univ. [Internet]. 2013. [Consultado 2021 ene 22];33:1181–84. Disponible en: https://pubmed.ncbi.nlm.nih.gov/23996762/.
Chen B, Cai HR, Xue S, You WJ, Liu B, Jiang HD. Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways. Respirology. [Internet]. 2016. [Consultado 2021 ene 22];21(6):1075–80. Disponible en: https://doi.org/10.1111/resp.12815.
Malhi H, Camilleri M. Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases. Curr Opin Pharmacol. [Internet]. 2017. [Consultado 2021 ene 22]; 37:80–6. Disponible en: https://doi.org/10.1016/j.coph.2017.09.008.
Nakada EM, Bhakta NR, Korwin-Mihavics BR, Kumar A, Chamberlain N, Bruno SR, et al. Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresponsiveness by inhibiting UPR transducers. JCI Insight. [Internet]. 2019. [Consultado 2021 ene 22];4(9):e98101. Disponible en: https://doi.org/10.1172/jci.insight.98101.
Chen B, You WJ, Xue S, Qin H, Zhao XJ, Zhang M, Liu XQ, et al. Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease. J Thorac Dis. [Internet]. 2016. [Consultado 2021 ene 22];8(11):3063-3074. Disponible en: https://doi.org/10.21037/jtd.2016.11.08.
Kosters A, Karpen Saul J. The role of inflammation in cholestasis – clinical and basic aspects. Semin Liver Dis. [Internet]. 2010. [Consultado 2021 ene 22];30(2): 186–94. Disponible en: https://doi.org/10.1055/s-0030-1253227.
Perng DW, Chen PK. The relationship between airway inflammation and exacerbation in chronic obstructive pulmonary disease. Tuberc Respir Dis. [Internet]. 2017. [Consultado 2021 ene 22];80:325-35. Disponible en: https://doi.org/10.4046/trd.2017.0085.
Jiang C, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest. [Internet]. 2015. [Consultado 2021 ene 22]; 125(1):386–402. Disponible en: https://doi.org/10.1172/JCI76738.
Wu Y-C, Hsu P-K, Su K-C, Liu L-Y, Tsai C-C Tsai, S-H, et al. Bile acid aspiration in suspected ventilator-associated pneumonia. Chest. [Internet]. 2009. [Consultado 2021 ene 22];136: 118–24. Disponible en: https://doi.org/10.1378/chest.08-2668.
De Luca D, Minucci A, Zecca E, Piastra M, Pietrini D, Carnielli VP, Zuppi C, Tridente A, Conti G, Capoluongo ED. Bile acids cause secretory phospholipase A2 activity enhancement, revertible by exogenous surfactant administration. Intensive Care Med. [Internet]. 2009. [Consultado 2021 ene 22];35:321–26. Disponible en: https://doi.org/10.1007/s00134-008-1321-3.
Autilio C, Shankar-Aguilera S, Minucci A, Touqui L, De Luca D. Effect of cooling on lung secretory phospholipase A2 activity in vitro, ex vivo, and in vivo. Am J Physiol Lung Cell Mol Physiol. [Internet]. 2019. [Consultado 2021 ene 22];316: L498–L505. Disponible en: https://doi.org/10.1152/ajplung.00201.2018.
Perng DW, Chang KT, Su KC, Wu YC, Wu MT, Hsu WH, et al. Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation. Chest. [Internet]. 2007. [Consultado 2021 ene 22];132:1548-56. Disponible en: https://doi.org/10.1378/chest.07-1373.
Su KC, Wu YC, Chen CS, Hung MH, Hsiao YH, Tseng CM, et al. Bile acids increase alveolar epithelial permeability via mitogen-activated protein kinase, cytosolic phospholipase A2, cyclooxygenase-2, prostaglandin E2 and junctional proteins. Respirology. [Internet]. 2013. [Consultado 2021 ene 22];18:848-56. Disponible en: https://doi.org/10.1111/resp.12086.
Perng DW, Wu YC, Tsai CC, Su KC, Liu LY, Hsu WH, et al. Bile acids induce CCN2 production through p38 MAP kinase activation in human bronchial epithelial cells: a factor contributing to airway fibrosis. Respirology. [Internet]. 2008. [Consultado 2021 ene 22];13:983-9. Disponible en: https://doi.org/10.1111/j.1440-1843.2008.01402.x.
Oyarzún GM. Función respiratoria en la senectud. Rev Méd Chile. [Internet]. 2009. [Consultado 2021 ene 22];137: 411-8. Disponible en: https://dx.doi.org/10.4067/S0034-98872009000300014.
Polkowska G, Polkowski W, Kudlicka A, Wallner G, ChrzastekSpruch H. Range of serum bile acid concentrations in neonates, infants, older children, and in adults. Med Sci Monit. [Internet]. 2001[Consultado 2021 ene 22];7,Suppl1: 268 –70. Disponible en: https://pubmed.ncbi.nlm.nih.gov/12211734/.
Zecca E, Costa S, Lauriola V, Vento G, Papacci P, Romagnoli C. Bile acid pneumonia: a "new" form of neonatal respiratory distress syndrome?. Pediatrics. [Internet]. 2004. [Consultado 2021 ene 22];58:44-7;114(1):269-72. Disponible en: https://doi.org/10.1542/peds.114.1.269.
Kaneko T, Satot Katsuyatt, et al. Surfactant therapy for pulmonary edema due to intratracheally infected bile acid. Crit Care Med. [Internet]. 1990. [Consultado 2021 ene 22];18:77-83. Disponible en: https://doi.org/10.1097/00003246-199001000-00017.
Zhang D, Li S, Wang N, Zhang Z, Feng Y, et al. The cross-talk between gut microbiota and lungs in common lung diseases. Front Microbiol. [Internet] 2020. [Consultado 2021 ene 22]; 11, 301. Disponible en: https://doi.org/10.3389/fmicb.2020. 00301.
Dumas A, Bernard L, Poquet Y, Villarino GL, Neyrolles O, et al. The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases. Cell Microbiol. [Internet] 2018 [Consultado 2021 ene 22];20(12):e12966. Disponible en: https://doi.org/10.1111/cmi.12966.
Beaudoin , J.J., Bezençon, J., Sjöstedt, N., Fallon, J.K., Brouwer, K. L.R. Role of Organic Solute Transporter Alpha/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions. Toxicoll Sc. [Internet] 2020 [Consultado 2021 ene 22];176(1),34–45. Disponible en: https://doi.org/10.1093/toxsci/kfaa052
Huang D, Xiong M, Xu X , Wu X , Xu J , Cai X, Lu L , ZHou H. Bile acids elevated by high-fat feeding induce endoplasmic reticulum stress in intestinal stem cells and contribute to mucosal barrier damage. Biochem Biophys Res Commun. [Internet] 2020 [Consultado 2021 ene 22];529(2):289-95. Disponible en: https://doi.org/10.1016/j.bbrc.2020.05.226.
Vítek L. Bile acid malabsorption in inflammatory bowel disease. Inflamm Bowel Dis. [Internet] 2015 [Consultado 2021 ene 22];21:476–483. Disponible en: https://doi.org/10.1097/MIB.0000000000000193.
Su KC, Wu YC, Chen CS, Hung MH, Hsiao YH, Tseng CM, Chang SC, Lee YC, Perng DW. Bile acids increase alveolar epithelial permeability via mitogen-activated protein kinase, cytosolic phospholipase A2, cyclooxygenase-2, prostaglandin E2 and junctional proteins. Respirology. [Internet] 2013 [Consultado 2021 ene 22];18(5):848-56. Disponible en: https://doi.org/doi: 10.1111/resp.12086.
Desai M, Mathur B, Eblimit Z, Vasquez H, Taegtmeyer H Karpen S, Penny D J, Moore DD, Anakk S. Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology. [Internet] 2017 [Consultado 2021 ene 22];65(1): 189–201. Disponible en: https://doi.org/10.1002/hep.28890
Musso, G., Cassader, M., Cohney, S.,Michieli, F. D., Pinach, S., Saba, F., Gambino, R. Fatty liver and chronic kidney disease: novel mechanisticinsights and therapeutic opportunities. Diabetes Care. [Internet] 2016 [Consultado 2021 ene 22];39:1830–1845. Disponible en: https://doi.org/10.2337/dc15-1182.
Qin, Pu, Xiaoyan Tang, M. Merle Elloso, and Douglas C. Harnish. Bile acids induce adhesion molecule expression in endothelial cells through activation of reactive oxygen species, NF-B, and p38. Am J Physiol Heart Circ Physiol. [Internet] 2006 [Consultado 2021 ene 22];291:H741–H747. Disponible en: https://doi.org/10.1152/ajpheart.01182.2005.
Aktas B, Aslim B. Gut-lung axis and dysbiosis in COVID-19. Turk J Biol. [Internet]. 2020. [Consultado 2021 ene 22];44:265-72. Disponible en: https://doi.org/10.3906/biy-2005-102 .
García MG, Fonte GL. Algunas consideraciones sobre el empleo de probióticos antes, durante y después de la infección por SARS-CoV-2. Act Med. [Internet]. 2020. [Consultado 2021 ene 22];21(3):e131. Disponible en: http://www.revactamedica.sld.cu/index.php/act/article/view/131.
Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. [Internet]. 2020. [Consultado 2021 ene 22];10(2): 02-8. Disponible en: https://doi.org/10.1016/j.jpha.2020.03.001.
Musa S. Hepatic and gastrointestinal involvement in coronavirus disease 2019 (COVID-19): What do we know till now? Arab J Gastroenterol. [Internet]. 2020 [Consultado 2021 ene 22];21(1):3-8. Disponible en: https://doi.org/10.1016/j.ajg.2020.03.002.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. [Internet]. 2020 [Consultado 2021 ene 22];579(7798):270-273. Disponible en: https://doi.org/10.1038/s41586-020-2012-7.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. [Internet]. 2020 [Consultado 2021 ene 22];8(4):420-22. Disponible en: https://doi.org/10.1016/S2213-2600(20)30076-X.
Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. [Internet]. 2020 [Consultado 2021 ene 22];26(7):1017-32. Disponible en: https://doi.org/10.1038/s41591-020-0968-3.
Adachi T, Chong JM, Nakajima N, Sano M, Yamazaki J, Miyamoto I, et al. Clinicopathologic and Immunohistochemical Findings from Autopsy of Patient with COVID-19, Japan. Emerg Infect Dis. [Internet]. 2020 [Consultado 2021 ene 22];26(9):2157–61. Disponible en: https://doi.org/10.3201/eid2609.201353.
Capó de Paz V, Borrajero Martínez I, Montero González T, Hurtado de Mendoza Amat J, de Armas Rodríguez Y, Domínguez Alvarez C. Hallazgos de autopsias de 50 fallecidos con SARS-CoV-2 en Cuba entre abril y septiembre de 2020. [Internet]. 2021 [Consultado 2021 ene 22];11(2): [aprox. 0 p.]. Disponible en: http://revistaccuba.sld.cu/index.php/revacc/article/view/994
Yang D, Xing Y, Song X, Qian Y. The impact of lung microbiota dysbiosis on inflammation. Immunology. [Internet]. 2020. [Consultado 2021 ene 22];159(2):156-66. Disponible en: https://doi.org/10.1111/imm.13139.
Feng G, Zheng KI, Yan Q-Q, Rios RS, Targher G, et al. COVID-19 and liver dysfunction: current insights and emergent therapeutic strategies. J ClinTransl Hepat. [Internet]. 2020. [Consultado 2021 ene 22];8 (1):18-24. Disponible en: https://doi.org/10.14218/JCTH.2020.00018.
Hanada S, Pirzadeh M, Carver KY, Deng JC. Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. Front Immunol. [Internet]. 2018. [Consultado 2021 ene 22];9:1-15. Disponible en: https://doi.org/10.3389/fimmu.2018.02640
Abdulrab S, Al-Maweri S, Halboub E. Ursodeoxycholic acid as a candidate therapeutic to alleviate and/or prevent COVID-19-associated cytokine storm. Med Hypotheses. [Internet]. 2020 [Consultado 2021 ene 22];143:109897. Disponible en: https://doi.org/10.1016/j.mehy.2020.109897.
Subramanian S, Iles T, Ikramuddin S, Steer CJ. Merit of an Ursodeoxycholic Acid Clinical Trial in COVID-19 Patients. Vaccines [Internet]. 2020 [Consultado 2021 ene 22];8(2):320. Disponible en: https://doi.org/10.3390/vaccines8020320.
Işık S, Karaman M, Çilaker Micili S, Çağlayan-Sözmen Ş, Bağrıyanık HA, Arıkan-Ayyıldız Z, et al. Beneficial effects of ursodeoxycholic acid via inhibition of airway remodelling, apoptosis of airway epithelial cells, and Th2 immune response in murine model of chronic asthma. Allergol Immunopathol [Internet]. 2017 [Consultado 2021 ene 22];45(4):339-349. Disponible en: https://doi.org/10.1016/j.aller.2016.12.003.
Razori MV, Maidagan PM, Ciriaci N, Andermatten RB, Barosso IR, Martín PL, Basiglio CL, Sánchez Pozzi EJ, Ruiz ML, Roma MG. Anticholestatic mechanisms of ursodeoxycholic acid in lipopolysaccharide-induced cholestasis. Biochem Pharmacol. [Internet]. 2019 [Consultado 2021 ene 22];168:48-56. Disponible en: doi: https://doi.org/10.1016/j.bcp.2019.06.009.
Brevini T, Maes M, Webb GJ, Gelson WTH, Forrest S, Mlcochova P, et al. FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome. BioRxiv. [Internet] 2021[Consultado en Ags 2021]; preprint: Disponible en: https://doi.org/10.1101/2021.06.06.446781.
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial 4.0 Internacional.
La revista está: Certificada por el CITMA
La revista es de acceso abierto y gratuito.