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The Possible Role of Lovastatin in Severe Acute Respiratory Syndrome (SARS)
- Chih-Yuan Wang, 100, Taipei, Taiwan (11 May 2003)
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Is the environmental pollution in China the principle cause for SARS deaths?
- Richard G Fiddian-Green (12 May 2003)
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Chih-Yuan Wang, Director, Division of Endocrinology Far-Eastern Memorial Hospital, 100, Taipei, Taiwan, 100, Taipei, Taiwan
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Sir--Severe acute respiratory syndrome (SARS), due to previously unknown coronaviruses, is a highly infectious disease in Taiwan, Hong-Kong and China. Medical workers in Emergency Services or outpatient departments are high risk groups for contagious or droplet infection. Preventive antiviral therapy should be very important for first-line medical workers or high-risk patients. WHO even warns that death rate of SARS may reach 10 to 15% 1, especially in aged patients. Lovastatin and other 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been widely used to treat hypercholesterolemia and reduce cardiovascular morbidity 2. These drugs also have anti- inflammatory effects to block cellular isoprenylation of proteins, including Ras and Rho, which influence various biological functions in eukaryotic cells 3. Lovastatin is usually used in patients with hyperlipidemia to decrease the levels of cholesterol. Meanwhile, cholesterol is an important part in cell membrane, called lipid rafts, and cholesterol to phospholipid ratio in cell membranes influences the stability of "lipid rafts". Lipid rafts may play an important role between virus and cell membrane. It has been estimated that the major part of cell membrane surface area (>50%) could actually be covered by rafts. A high cholesterol to phospholipid ratio could be critical for the stability of virus particles 4. Gower TL and Graham BS have demonstrated that the F-glycoprotein from respiratory syncytial virus (RSV) may interact with RhoA, and F is thought to be required for virus entry into cells 5. Activation of RhoA in a cell may increase production of interleukin-1-beta (IL-1£]), IL-6 and IL-8, and they alter cytoskeletal structure of actin stress fibers and formation of focal adhesion plaque 5. They also showed that lovastatin can inhibit RSV replication in vitro and in mice via disrupting cholesterol-rich rafts, which can interfere with virus entry and fusion. Their data suggest that lovastatin should be considered for evaluation as a preventive antiviral therapy for RSV. Coronavirus has a "spike" glycoprotein on its surface that may behave like the F protein of RSV or the gp41 of human immunodeficiency virus. It could mediate membrane fusion with cell membranes, and result in cellular syncytium formation. Coronavirus could be a good candidate for interacting with lipid rafts, but this has not been proven. On the other hand, update treatment of SARS seems to be empirical. Ribavirin, high-dose corticosteroid and supportive treatment are the main therapeutic strategies. Steroids were usually used for acute respiratory distress syndrome (ARDS) because of cytokines "storm", and fibroproliferative disorders in lung may occur. However, apparent benefits of steroid treatment may be incorrect, as in infection of RSV 6. Tan A, et al had found that lovastatin may potently inhibit inflammation and fibrous granulation tissue formation in fibroproliferative disorders 7. Since coronaviruses are important pathogens for SARS, and treatment of such a new disease is usually empirical. We must try to find more therapies for this potentially fatal disease. Although lovastatin has dose -related side effects including increases in serum transaminase values or rhabdomyolysis. We may suggest that the widely used lovastatin or other HMG Co-A reductase inhibitors should receive more tests in virological laboratories. Chih-Yuan Wang, M.D., PhD., Tien-Chun Chang M.D., PhD.
Acknowledge: We have sent an e-mail for Dr. Barney Graham, the Chief of Viral Pathogenesis Laboratory and Clinical Trials Core, VRC/NIAID/NIH, for his experience of lovastatin in RSV. We thank Dr. Graham for his expert and helpful discussion. 1. Parry J. WHO warns that death rate from SARS could reach 10 %. BMJ 2003;326:999. 2. Scandinavian Simvastatin Survival Study Group. 1994 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383¡V89. 3. Goldstein JL, Brown MS. 1990 Regulation of the mevalonate pathway. Nature 343:425-30. 4. Maarit Suomalainen. Lipid rafts and assembly of enveloped viruses. Traffic 2002;3:705-09. 5. Gower TL, Graham BS. Antiviral activity of lovastatin against respiratory syncytial virus in vivo and in vitro. Antimicrob Agent Ch 2002;45:1231-1237. 6. Tomlison B, Cockram C. SARS: experience at Prince Wales Hospital, Hong- Kong. Lancet 2003;361:1486-87. 7. Tan A, Levrey H, Dahm C, et al. Lovastatin induces fibroblast apoptosis in vitor and in vivo: a possible therapy for fibroproliferative disorders. Am J Respir Crit Care Med 1999;159:220-27. Competing interests: None declared |
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Richard G Fiddian-Green, None None
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Have the majority of the serious respiratory infections and deaths that have occurred in patients with SARS in China (1) been caused by a coronaviral infection or by a coronoviral infection compounding an underlying impairment of mitochondrial oxidative phosphorylation caused by environmental pollution? An impairment of mitochondrial oxidative phosphorylation is believed to be the primary cause of organ dysfunctions and failures responsible for the deaths in the critically ill (2,3). In other words might the real problem in China be its environmental pollution? According to John Walsh, who wrote the chapter on peptic ulceration in Kelley's Textbook of Internal Medicine, H pylori is found in almost 100% of patients in lesser developed countries, no doubt including China (4). What is more the 100% prevalence is apparent soon after birth and persists in all age groups. In developed countries, however, H pylori is far less common especially in the young, the prevalence increasing as the age of the patients increases. H pylori is a microaerophilic organism that requires 10% CO2 to grow in culture (5). In healthy subjects the intragastric pCO2 is 40mmHg, which is equivalent to 5% CO2 and tends to remain at that level under fasting conditions (6). The pCO2 in the duodenal bulb may rise intermittently and very transiently above 40 mmHg after eating but for the most part the pCO2 remains the same as that in arterial blood (7,8). This pCO2 is too low for H pylori to grow and thrive in culture and presumably, therefore, in the stomach. In which case there must be a cause for the abnormal elevation in intragastric pCO2 required for H pylori to grow and thrive. The pCO2 rises above the arterial pCO2 in low flow states. It may also rise t6o abnormal levels when mitochondrial oxidative phosphorylation is impaired by other means for CO2 is released by the buffering of protons accumulating with unreversed ATP hydrolysis (1,2). Mitochondrial dysfunction increases with advancing age. If accompanied by a rise in intragastric pCO2 this could account for the increase in prevalence in H pylori with advancing age in developed countries. The intragastric pCO2 is abnormally elevated in fasting patients with peptic ulcers (9,10). The most important cause for this elevation may be smoking, but others causes of impaired mitochondrial oxidative phosphorylation might also be responsible (11). The principle cause of the hypothetical elevation in intragastric pCO2 prevalent in the majority of people living in lesser developed countries cannot be smoking, unless it is second hand smoke, for H pylori infections develop so early in life. An envioronmental cause is more likely, be this carbon monoxide and/or other air pollutants or cyanide and/or other mitochondrial toxins, such as those commonly present in pesticides contaminating ground water and food. Another possible cause for the hypothetical elevation in intragastric pCO2 in people living in lesser developed countries is cytokine release induced by the translocation of endotoxin precipitated by mucosal disruption caused by intestinal parasites and/or recurrent bouts of diarrhoea and dyentery. If this hypothesis is correct then lesser developed countries, including China, that fail to take proper care of their environments are more likely to experience epidemics of serious and even fatal respiratory infections such as SARS. The hypothesis, that the ambient pCO2 in the stomachs of people living in lesser developed countries is higher than that in people living in developed countries, is easy to test. It would be more appropriate, however, to measure the intramucosal pH for this provides an objective measure of tissue energetics the ultimater determinant of cellular fiunction and viability (12). The intramucosal PCO2 does not unless the impairment is very severe. 1. WHO warns that death rate from SARS could reach 10% Jane Parry BMJ 2003; 326: 999a 2. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid- base balance. Br J Anaesth. 1995 May;74(5):591-606. Review. 3. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement. Chest. 1999 Dec;116(6):1839-41 4. Textbook of Internal Medicine, 4th Ed. Author, H. David Humes. Publisher, Lippincott Williams & Wilkins. Pub Year, 2000. 5.Heard SO, Helsmoortel CM, Kent JC, Shahnarian A, Fink MP. Gastric tonometry in healthy volunteers: effect of ranitidine on calculated intramural pH. Crit Care Med. 1991 Feb;19(2):271-4. 6. Burns BP, Hazell SL, Mendz GL. Acetyl-CoA carboxylase activity in Helicobacter pylori and the requirement of increased CO2 for growth. Microbiology. 1995 Dec;141 ( Pt 12):3113-8. 7. Dorricott NJ, Fiddian-Green RG, Silen W. Mechanisms of acid disposal in canine duodenum. Am J Physiol. 1975 Jan;228(1):269-75. 8. Fiddian-Green RG, Silen W. Mechanisms of disposal of acid and alkali in rabbit duodenum. Am J Physiol. 1975 Dec;229(6):1641-8. 9. Rune SJ. The duodenal PCO2 in duodenal ulcer patients and normal subjects. Acta Hepatogastroenterol (Stuttg). 1972 Sep-Oct;19(5):386-7. 10. Elder JB, Hearn AR.Intragastric PCO2 in man and calculated gastric bicarbonate concentrations: effect of carbenoxolone sodium. Scand J Gastroenterol Suppl. 1980;65:19-27. 11. Smoking, infantile hypertrophic pyloric stenosis, and peptic ulceration Richard G Fiddian-Green bmj.com/cgi/eletters/325/7371/1011#29078, 24 Jan 2003 12. Rolett EL, Azzawi A, Liu KJ, Yongbi MN, Swartz HM, Dunn JF.Critical oxygen tension in rat brain: a combined (31)P-NMR and EPR oximetry study. Am J Physiol Regul Integr Comp Physiol. 2000 Jul;279(1):R9-R16 Competing interests: None declared |
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