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074 influenza infection effects

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074 influenza infection effects

  1. 1. Influenza Infection Exerts Prominent Inflammatory and Thrombotic Effects on Atherosclerotic Plaques of Apo E-Deficient Mice Silvio Litovsky, Philip Wyde, Mohammad Madjid, Adeeba Akhtar, Sameh Naguib, Said Siadaty, Susan Sanati, Ward Casscells, Morteza Naghavi, Center for Vulnerable Plaque Research, University of Texas-Houston, and Texas Heart Institute, Houston, Texas.
  2. 2. Outline: Infection/ inflammation and atherosclerosis Influenza and complications of atherosclerosis Influenza on aged Apo E-deficient mice
  3. 3. Am J Epidermiol. 1998;148,10:937-948 Introduction of antibiotics and reduction in CAD (hypothetical)
  4. 4. Am J Epidermiol. 1998;148,10:937-948 Aorta of rabbits experimentally inoculated with infectious agents Streptococcus C. pneumoniae
  5. 5. Effect of INF-γ on the development of atherosclerosis in young Apo E- deficient mice.
  6. 6. Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice. Whitman SC, Ravisankar P, Elam H, Daugherty A. A role for interferon-gamma (IFN-gamma) has been implied in the atherogenic process. To determine whether exogenously administered IFN-gamma exerts an effect on the development of atherosclerosis, we intraperitoneally administered either recombinant IFN-gamma (100 U/g body weight) or phosphate buffered saline daily for 30 days to atherosclerosis-susceptible apolipoprotein E-/- mice (16-week-old male mice, n = 11 per group) fed a normal diet. Atherosclerotic lesion size was quantified in the ascending aorta. The number of T lymphocytes and major histocompatibility complex (MHC) class II-positive cells within lesions were also quantified in this region. IFN-gamma administration reduced serum cholesterol concentrations by 15% (P = 0.02). For both groups, the majority of cholesterol was present in very low density lipoproteins, which were modestly reduced in mice receiving IFN-gamma. Despite the decrease in serum cholesterol concentrations, IFN-gamma injections significantly increased lesion size twofold compared to controls (119,980 +/- 18, 536 vs. 59,396 +/- 20,017 micrometer(2); P = 0.038). IFN-gamma also significantly increased the mean number of T lymphocytes (19 +/- 4 vs. 7 +/- 1 cells; P = 0.03) and MHC class II-positive cells (10 +/- 3 vs. 3 +/- 1 cells; P = 0.04) within lesions. These data lend further support to a pro-atherogenic role of IFN-gamma.
  7. 7. Outline Influenza and complications of atherosclerosis
  8. 8. Cir Circulation. 2000;102:3039-30045
  9. 9. Outline Influenza on aged Apo E-deficient mice
  10. 10. Background • Influenza infection is associated with elevated C-reactive protein and serum amyloid A, especially in the elderly • HDL loses its anti-inflammatory properties and LDL becomes more susceptible to oxidation during influenza infection* • Mouse is a standard model for influenza and the apo E K/O mouse is a model for atherosclerosis • LD50 in apo E K/O mouse is comparable to LD50 of wild type • Maximal viral titers in the lung occur on day 4 after inoculation; animals usually die between days 4 - 10. (Van Lenten, Circulation 2001;103:2283-8)
  11. 11. Methods • 33 apo E K/O mice of either sex 2-2.5 years old and 10 age- matched C57 BL were intranasally injected with 1LD50 of influenza A virus • Body weight, heart rate and O2 saturation determined at inoculation, day 3, day 5 and at time of sacrifice • Sacrificed at days 3, 5, 10 and 15. In case of spontaneous death, autopsy was performed within 12 hours • Virus quantification on homogenized lungs determined on day 4 by hemagglutination • RT-PCR for the presence of influenza mRNA in the aorta of 2 animals • Aorta up to the level of the renal arteries were excised, fixed in formalin and processed
  12. 12. Results • Hemagglutinating virus isolated from every virus- inoculated mouse. • No clear evidence of influenza RNA on aortic samples • 13 animals died between days 4 and 10. All inoculated animals lost weight. Eleven infected (7 sacrificed and 4 fatalities) showed striking intimal infiltrates. Nine out of the 11 with intimal infiltrates died or were sacrificed on day 10 +/- 1 day.
  13. 13. Smooth muscle actin Mac-1 CD4
  14. 14. Cytokine-SPIO Protocol •Purpose: To enhance macrophage homing to plaque and monitor it by SPIO. Compare the iron particles present in macrophages of apo E-deficient atherosclerotic plaques under baseline conditions (control group) and after the administration of TNF-α, IL-1β and IFN-γ (influenza simulated group).
  15. 15. Cytokine-SPIO Protocol •Protocol: Eight retired female breeders, approximately 12-month old were divided in 2 groups. Five received I.P. 0.2 µg each of mouse recombinant TNF- and IL-1ß; and 100 units/g INF-γ for six days; the 3 control received 0.5 mL saline containing 1% BSA. Three hours later, all the animals were I.V. injected with Feridex 1 mMol/kg of iron. Seven days later, the recipients were euthanized with CO2 and perfused under physiological pressure. The entire aorta up to the iliac bifurcation was formalin-fixed, serially sectioned transversally and stained for H&E and iron.
  16. 16. Iron Staining H&E Staining Apo E-deficient mouse injected with SPIO No cytokines
  17. 17. Iron Staining H&E Staining Apo E-deficient mouse injected with SPIO No cytokines
  18. 18. Iron Staining H&E Staining Apo E-deficient mouse injected with SPIO Cytokines added
  19. 19. Iron Staining H&E Staining Apo E-deficient mouse injected with SPIO Cytokines added
  20. 20. Intramural coronary artery involvement Myocardial injury Apo E-deficient mouse injected with SPIO Cytokines added
  21. 21. Conclusion • Influenza A virus exerts prominent pro-inflammatory and pro-thrombotic effects in about one third of aged apo E K/O mice • Studies with longer follow-up periods are necessary to determine whether increased plaque burden and/or aneurysm formation occur • Significance of LD 50 dose is unclear for atherosclerosis. Other doses are being planned • Plaque inflammation as seen in this model has not been, to our knowledge, previously reported in experimental models of atherosclerosis
  22. 22. Conclusion Cytokine effect likely accounts, at least partially, for the effects of influenza infection on the atherosclerotic plaques
  23. 23. Acknowledgement James T Willerson, MD S Ward Casscells, MD Morteza Naghavi, MD Philip Wyde, PhD Mohammad Madjid, MD Adeeba Akhtar, MD Said Siadaty, MD