CYTOKINE STORM and the INFLUENZA PANDEMIC: Treatment Options?



ACE inhibitors and Angiotensin II Receptor Blockers:

Genectoy and co-workers implicated the Renin Angiotensin system (RAS) in the mediation of the cytokine storm,[1] and these researchers suggested a potential benefit for Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (ARBs). Researchers at Johns Hopkins found ACE to be associated with inflammatory lung pathologies. [2] Shigehara et al. of Sapporo medical University in Japan published research confirming that serum angiotensin-converting enzyme (ACE) was a useful marker for disease activity in cytokine-mediated inflammatory lung diseases. [3] Marshall and co-workers similarly found that angiotensin II was associated with cytokine-mediated lung injury [4] and these researchers suggested a role for ACE inhibitors.

Wang and co-workers published data that cytokine-mediated pulmonary damage (apoptosis of lung epithelial cells) in response to the pro-inflammatory cytokine TNF-alpha (implicated in the cytokine storm) requires the presence of angiotensin II, suggesting that ARBs might have clinical utility in this setting.[5]

Das published a review of ACE inhibitor and angiotensin-II receptor blocker use in a number of cytokine-mediated inflammatory pathologies and found that angiotensin II was a pro-inflammatory molecule and suggested that ACE inhibitors and Angiotensin receptor blockers could have theoretical benefit in downregulation of the cytokine storm.[6]

Eritoran

Eritoran is a compound that is currently (5/3/2013) under investigation as a treatment for sepsis. Cytokine storm is implicated in lethality from sepsis, and eritoran protects from "acute lung injury" associated with lethal cytokine storm. In one animal study, treatment with Eritoran significantly and dramatically reduced death from influenza viral infection in mice.[25] Lead author of the study Stephanie Vogel, Ph.D. is professor of Microbiology and Immunology at the University of Maryland, Baltimore).

Vitamin D:

Vitamin D reduces the risk of developing influenza [21,22], suppresses inflammatory cytokines [11, 12-14] and may suppress the cytokine storm associated with fatal cases of influenza [11,15]. Numerous studies have shown an increased risk for influenza when patients vitamin D levels decline. [16-20], and one recent study [23] found that risk was 36% higher for healthy people with vitamin D levels below 30 ng/ml. Additionally, a blinded, placebo controlled study conducted in 2005 found a direct correlation with with vitamin D supplementation and flu prevention [24].

Dosage: Vitamin D3 is the generally preferred form, and dosage may be in excess of 6,000 IU per day.
Holick (University of Boston) found that Vitamin D toxicity does not typically develop unless vitamin D intake exceeds 10,000 units per day or blood levels exceed 80 ng/mL (200 nmol/L).[7,8] And Hathcock and co-workers stated that the tolerable upper intake level of vitamin D intake should be revised from 2,000 IU/day to 10,000 IU/day. [7]

Holick suggests that optimum serum level of 25-hydroxyvitamin D is in the range of 30-50 ng/mL (75-125 nmol/L). [9] A study of elderly men and women by Dawson-Hughes et al suggested that levels of 25-hydroxyvitamin D above 45 ng/mL may be crucial for optimal health of all aging adults. [10]

REFERENCES

(1) Genctoy, G; B Altun et al. (February 2005). "TNF alpha-308 genotype and renin-angiotensin system in hemodialysis patients: an effect on inflammatory cytokine levels?". Artif Organs 29 (2): 174178.

(2) Moldobaeva, A; EM Wagner (December 2003). "Angiotensin-converting enzyme activity in ovine bronchial vasculature". J Appl Physiol (Department of Medicine, Johns Hopkins University) 95 (6): 22782284.

(3) Shigehara, K; N Shijubo et al. (April 2003). "Increased circulating interleukin-12 (IL-12) p40 in pulmonary sarcoidosis". Clin Exp Immunol (Sapporo Medical University School of Medicine) 132 (1): 152157.

(4) Marshall, RP; P Gohlke et al. (January 2004). "Angiotensin II and the fibroproliferative response to acute lung injury". Am J Physiol Lung Cell Mol Physiol (Royal Free and University College London Medical School) 286 (1): 156164. PMID 12754187.

(5) Wang, R; G Alam et al. (November 2000). "Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo". J Cell Physiol (The Cardiovascular Institute, Michael Reese Hospital and Medical Center) 185 (2): 253259. PMID 11025447.

(6) Das UN (May 2005). "Angiotensin-II behaves as an endogenous pro-inflammatory molecule". The Journal of the Association of Physicians of India 53: 4726.

(7) Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.

(8) Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006 Mar;81(3):353-73.

(9) Holick MF. The role of vitamin D for bone health and fracture prevention. Curr Osteoporos Rep. 2006 Sep;4(3):96-102.

(10) Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr. 1997 Jan;65(1):67-71

(11) Virol J. 2008;529.

(12) Blood 2005 Dec 15;106(13):4351-8

(13) Br J Nutr. 2005 Oct;94(4):483-92

(14) Mol Aspects med. 2008 Dec;29(6):369-75

(15) Mikrobiyol Bul. 2008 Apr;42(2):356-80 (16) Eur J Clin Nutr. 2004 Apr;58(4):563-7.

(17) Am J Clin Nutr. 2007 Sept;86(3):714-7.

(18) J Infect Dis. 2008 Mar 1;197(5)676-80.

(19) Eur J Clin Nutr. 2009 Apr;63(4):473-7

(20) Pediatr Pulmonol. 2009 Sept 10;44(10):981-8.

(21) Science News. 2006 Nov 11:312-3.

(22) J Nutr. 2005 Feb;135:(2):317-22.

(23) Arch Intern Med. 2009 Feb 23;169(4):384-90.

(24) Epidemiol Infect. 2007 Oct;135(7):1095-6.

(25) Shirley KA, Vogel SN, et al. The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature. 2013 May 1. PMID 23636320






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