Continuing Education: Review
Severe Acute Lung Injury Related to COVID-19 Infection: A Review and the Possible Role for Escin
Luca Gallelli MD, PhD,
Leiming Zhang MD, PhD,
Tian Wang MD, PhD,
Fenghua Fu MD, PhD,
Luca Gallelli MD, PhD
Department of Health Science, University of Catanzaro, Italy and Operative Unit of Clinical Pharmacology Mater Domini Hospital, Catanzaro, Italy
Search for more papers by this authorLeiming Zhang MD, PhD
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
Search for more papers by this authorTian Wang MD, PhD
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
Search for more papers by this authorCorresponding Author
Fenghua Fu MD, PhD
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
Corresponding Author:
Fenghua Fu, MD, PhD, School of Pharmacy, Yantai University, Yantai, 264005, China
Email: [email protected]
Search for more papers by this authorLuca Gallelli MD, PhD,
Leiming Zhang MD, PhD,
Tian Wang MD, PhD,
Fenghua Fu MD, PhD,
Luca Gallelli MD, PhD
Department of Health Science, University of Catanzaro, Italy and Operative Unit of Clinical Pharmacology Mater Domini Hospital, Catanzaro, Italy
Search for more papers by this authorLeiming Zhang MD, PhD
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
Search for more papers by this authorTian Wang MD, PhD
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
Search for more papers by this authorCorresponding Author
Fenghua Fu MD, PhD
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, China
Corresponding Author:
Fenghua Fu, MD, PhD, School of Pharmacy, Yantai University, Yantai, 264005, China
Email: [email protected]
Search for more papers by this authorAbstract
Acute lung injury (ALI) represents the most severe form of the viral infection sustained by coronavirus disease 2019 (COVID-19). Today, it is a pandemic infection, and even if several compounds are used as curative or supportive treatment, there is not a definitive treatment. In particular, antiviral treatment used for the treatment of several viral infections (eg, hepatitis C, HIV, Ebola, severe acute respiratory syndrome–coronavirus) are today used with a mild or moderate effect on the lung injury. In fact, ALI seems to be related to the inflammatory burst and release of proinflammatory mediators that induce intra-alveolar fibrin accumulation that reduces the gas exchange. Therefore, an add-on therapy with drugs able to reduce inflammation, edema, and cell activation has been proposed as well as a treatment with interferon, corticosteroids or monoclonal antibodies (eg, tocilizumab). In this article reviewing literature data related to the use of escin, an agent having potent anti-inflammatory and anti-viral effects in lung injury, we suggest that it could represent a therapeutic opportunity as add-on therapy in ALI related to COVID-19 infection.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- 1Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382(8): 727-733.
- 2Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020; 109:102433.
- 3Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review [published online ahead of print April 13, 2020]. JAMA. https://doi.org/10.1001/jama.2020.6019.
- 4Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020; 20(5): 269-270.
- 5Li G, Fan Y, Lai Y, et al. Coronavirus infections and immune responses. J Med Virol. 2020; 92(4): 424-432.
- 6Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools [published online ahead of print March 3, 2020]. Virol Sin. https://doi.org/10.1007/s12250-020-00207-4.
- 7Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect. 2020;pii: S0163-4453(20)30165-1.
- 8Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017; 39(5): 529-539.
- 9Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017; 39(5): 517-528.
- 10Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223): 497-506.
- 11Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229): 1054-1062.
- 12Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020; 46(5): 846-848.
- 13Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China [published online ahead of print March 13, 2020]. JAMA. https://doi.org/10.1001/jamainternmed.2020.0994
- 14Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395(10223): 507-513.
- 15Wygrecka M, Jablonska E, Guenther A, Preissner KT, Markart P. Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases. Thromb Haemostasis. 2008; 99(3): 494-501.
- 16Stinson SF, Ryan DP, Hertweck S, Hardy JD, Hwang-Kow SY, Loosli CG. Epithelial and surfactant changes in influenzal pulmonary lesions. Arch Pathol Lab Med. 1976; 100(3): 147-153.
- 17Burkhardt A. Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Resp Dis. 1989; 140(2): 513-524.
- 18Dang CV, Bell WR, Kaiser D, Wong A. Disorganization of cultured vascular endothelial cell monolayers by fibrinogen fragment D. Science. 1985; 227(4693): 1487-1490.
- 19Leavell KJ, Peterson MW, Gross TJ. The role of fibrin degradation products in neutrophil recruitment to the lung. Am J Resp Cell Mol Biol. 1996; 14(1): 53-60.
- 20Idell S, James KK, Levin EG, et al. Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest. 1989; 84(2): 695-705.
- 21Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229): 1033-1034.
- 22Sarzi-Puttini P, Giorgi V, Sirotti S, et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol. 2020; 38(2): 337-342.
- 23Zhou H, Li XL, Li B. Pay attention to 2019 coronavirus disease (COVID-19) induced sepsis immunosuppression. J Third Milit Med Univ. 2020; 42(6): 539-544.
- 24Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer. J Thorac Oncol. 2020; 15(5): 700-704.
- 25Liu Q, Wang RS, Qu GQ, et al. General view of the systemic anatomy of a dead cadaver resulted from COVID-19. J Foren Med. 2020; 36(1): 21-23.
- 26Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. J Lancet Respir Med. 2020; 8(4): 420-422.
- 27Yao XH, Li TY, He ZC, et al. A pathological report of three COVID-19 cases by minimally invasive autopsies. Chinese J Pathol. 2020; 49: E009.
- 28Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Milit Med Res. 2020; 7(1): 4.
- 29Li H, Wang YM, Xu JY, Cao B. Potential antiviral therapeutics for 2019 novel coronavirus. Chinese J Tubercu Resp Dis. 2020; 43(3): 170-172.
- 30Arabi YM, Asiri AY, Assiri AM, et al. Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-beta1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial. Trials. 2020; 21(1): 8.
- 31Arabi YM, Alothman A, Balkhy HH, et al. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-beta1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials. 2018; 19(1): 81.
- 32Habibzadeh P, Stoneman EK. The novel coronavirus: a bird's eye view. Int J Occup Environ Med. 2020; 11(2): 65-71.
- 33Cao B, Wang Y, Wen D, et al. A Trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 [published online ahead of print March 18, 2020]. N Engl J Med. 2020; 382(19): 1787-1799.
- 34Deng L, Li C, Zeng Q, et al. Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: a retrospective cohort study. J Infect. 2020;pii: S0163-4453(20)30113-30114.
- 35Du YX, Chen XP. Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection [published online ahead of print April 4, 2020]. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.1844.
- 36Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30(3): 269-271.
- 37Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infect Dis. 2006; 6(2): 67-69.
- 38Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? [published online ahead of print March 12, 2020] Int J Antimicrob Agents. https://doi.org/10.1016/j.ijantimicag.2020.105938.
- 39Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003; 3(11): 722-727.
- 40Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression [published online ahead of print March 20, 2020]. J Antimicrob Chemother. https://doi.org/1093/jac/dkaa114.
- 41Duan YJ, Liu Q, Zhao SQ, et al. The trial of chloroquine in the treatment of corona virus disease 2019 (COVID-19) and its research progress in forensic toxicology. J Foren Med. 2020; 36(2): 1-7.
- 42Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. [published online ahead of print March 20, 2020] https://doi.org/10.1016/j.ijantimicag.2020.105949.
- 43Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ. 2020; 192(17): E450-E453.
- 44Williamson BR, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2 [published online ahead of print April 15, 2020]. BioRxiv. https://doi.org/10.1101/2020.04.15.043166.
- 45Chen YW, Yiu CB, Wong KY. Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. Version 2. F1000Res. 2020; 9:129. https://doi.org/10.12688/f1000research.22457.2. eCollection 2020.
- 46Hui DS, Lee N, Chan PK, Beigel JH. The role of adjuvant immunomodulatory agents for treatment of severe influenza. Antiviral Res. 2018; 150: 202-216.
- 47Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018; 23(8): 943-947.
- 48Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Rev Clin Immunol. 2019; 15(8): 813-822.
- 49Li W, Zhang C, Sui J, et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 2005; 24(8): 1634-1643.
- 50Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426(6965): 450-454.
- 51Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005; 309(5742): 1864-1868.
- 52Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020; 395(10223): e30-e31.
- 53Gharebaghi R, Heidary F, Moradi M, Parvizi M. Metronidazole: a potential novel addition to the COVID-19 treatment regimen. Arch Acad Emerg Med. 2020; 8(1):e40.
- 54Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004; 136(1): 95-103.
- 55He L, Ding Y, Zhang Q, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS. J Pathol. 2006; 210(3): 288-297.
- 56Pelaia G, Gallelli L, D'Agostino B, et al. Effects of TGF-beta and glucocorticoids on map kinase phosphorylation, IL-6/IL-11 secretion and cell proliferation in primary cultures of human lung fibroblasts. J Cell Physiol. 2007; 210(2): 489-497.
- 57Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020; 323(11): 1061-1069.
- 58Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020; 395(10223): 473-475.
- 59Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006; 3(9):e343.
- 60Lansbury LE, Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of influenza: an updated cochrane systematic review and meta-analysis [published online ahead of print November 15, 2019]. Crit Care Med. 2020; 48(2): e98-e106.
- 61Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018; 197(6): 757-767.
- 62 World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance. https://apps.who.int/iris/handle/10665/330893. Published 2020. Accessed January 28, 2020.
- 63Runfeng L, Yunlong H, Jicheng H, et al. Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2). Pharm Res. 2020; 56:104761. https://doi.org/10.1016/j.phrs.2020.104761
- 64Xin W, Zhang L, Sun F, et al. Escin exerts synergistic anti-inflammatory effects with low doses of glucocorticoids in vivo and in vitro. Phytomedicine. 2011; 18(4): 272-277.
- 65Domanski D, Zegrocka-Stendel O, Perzanowska A, et al. Molecular mechanism for cellular response to beta-escin and its therapeutic implications. PloS One. 2016; 11(10):e0164365.
- 66Montopoli M, Froldi G, Comelli MC, Prosdocimi M, Caparrotta L. Aescin protection of human vascular endothelial cells exposed to cobalt chloride mimicked hypoxia and inflammatory stimuli. Planta Med. 2007; 73(3): 285-288.
- 67Chen C, Wang S, Chen J, et al. Escin suppresses HMGB1-induced overexpression of aquaporin-1 and increased permeability in endothelial cells. FEBS Open Bio. 2019; 9(5): 891-900.
- 68Wu CY, Jan JT, Ma SH, et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci U S A. 2004; 101(27): 10012–10017.
- 69Salinas FM, Vazquez L, Gentilini MV, et al. Aesculus hippocastanum L. seed extract shows virucidal and antiviral activities against respiratory syncytial virus (RSV) and reduces lung inflammation in vivo. Antiviral Res. 2019; 164: 1-11.
- 70Michelini FM, Alche LE, Bueno CA. Virucidal, antiviral and immunomodulatory activities of beta-escin and Aesculus hippocastanum extract. J Pharm Pharmacol. 2018; 70(11): 1561-1571.
- 71Wang B, Mao X, Zhu J. beta-aescin alleviates acute lung injury induced by lipopolysaccharide by inhibiting lipid peroxidation and inflammation in mice. Chinese J Cell Mol Immunol. 2018; 34(7): 600-604.
- 72Xin W, Zhang L, Fan H, Jiang N, Wang T, Fu F. Escin attenuates acute lung injury induced by endotoxin in mice. Eur J Pharm Sci 2011; 42(1-2): 73-80.
- 73Muller-Redetzky H, Kellermann U, Wienhold SM, et al. Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis. Anesthesiology. 2020; 132(4): 795-807.
- 74Fu F, Wang Z, Tian J, Jiang W, Wang C. Application of aescinate and its salts in the preparation of drugs for treating acute inflammation of lung. Patent of China. 2009; ZL03136127.7:2009-2006-2024.
- 75Wei T, Tong W, Wen-ping S, et al. The impact of sodium aescinate on acute lung injury induced by oleic acid in rats. Exp Lung Res. 2011; 37(10): 585-599.
- 76Huang S, Meng L, Wang Z, Ling T, Zeng Z. The intervening effect of sodium aescinate on pulmonary fibrosis in ALI rats. J Guangdong Pharm Univ. 2018; 34(1): 59-63.
- 77Xiao X. Fighting against SARS by traditional Chinese medicine integrated efficiently with Chinese materia medica. Chinese Tradi Herbal Drug. 2003; 34(7): 669-671.
- 78Liu C, Hu P, Li C, Wang X, Xiao XT. Therapeutic value of aescine in traumatic acute lung injury. J Trauma Surg. 2013; 15(6): 497-499.
- 79Zhang K, Lu Y, Li D, Liang S. The effect of Shunqi Huoxue decoction combined with β-sodium aescinate in the treatment of acute lung injury caused by thoracic trauma and influences on serum ferritin superoxide dismutase and lung function. Shaanxi J Tradi Chinese Med. 2018; 39(12): 1798-1801.
- 80Liu W, Liang Y, Wang L, Hu J, Li Z. Effect of β-sodium aescinate on 35 cases of pulmonary contusion. Hebei Med J. 2009; 31(22): 3074-3075.
- 81Wang H, Fu L, Wang H, Li Q. Clinical study on the prevention of acute radiation lung injury by β-aescin sodium. Jiangsu Tradi Chinese Med. 2008; 40(10): 39-40.
- 82Wang Z, Gao Q. Clinical analysis on the treatment of 60 cases of increased thoracic drainage after thoracotomy with sodium aescinate. Shandong Med J. 2012; 52(13): 9.
- 83Wang Z, Zhao F, Jiang G, et al. Clinical study of hyperthermia combined with Aescinate Sodium for Injection in treating pneumonia-like pleural effusion. China Med Herald. 2019; 16(8): 113-116.
- 84Wang Y, Liu Z, Zhang F, Wu X, Guo W, Liu M. Effects of sodium aescinate on cytokine during acute exacerbation in patients with chronic obstructive pulmonary disease. China J Mode Med. 2012; 22(28): 51-54.
- 85Wang Y, Liu Z, Zhang F, et al. Effects of sodium aescinate combined with tiotropium bromide on pulmonary function and inflammatory mediators in patients with acute exacerbation of COPD. Chinese J Gerontol. 2013; 33(19): 4742-4743.
- 86Hao G, Qin J. A randomized controlled study of sodium aescinate on chronic pulmonary heart with peripheral edema. Chinese J Coal Ind Med. 2008; 2008(11): 8.
- 87Tang S, Gong F, Wu Z. Clinical trial of β-sodium aescinate injection in the treatment of chronic obstructive pulmonary disease complicated with pneumocardial disease and heart failure. Chin J Clin Pharmacol. 2019; 35(21): 2651-2654.
- 88Pan L, Niu J, Wang Z, Zhang L, Fu F. Effect of escin on acute inflammation of lung. China Pharmacist. 2010; 13(3): 321-323.
- 89Russell D, Blain PG, Rice P. Clinical management of casualties exposed to lung damaging agents: a critical review. Emergency medicine journal: EMJ. 2006; 23(6): 421-424.
- 90He DK, Shao YR, Zhang L, et al. Adenovirus-delivered angiopoietin-1 suppresses NF-kappaB and p38 MAPK and attenuates inflammatory responses in phosgene-induced acute lung injury. Inhal toxicol. 2014; 26(3): 185-192.
- 91Gallelli L. Escin: a review of its anti-edematous, anti-inflammatory, and venotonic properties. Drug Des Devel Ther. 2019; 13: 3425-3437.
