Cell Stress and Chaperones

, Volume 17, Issue 2, pp 255–265 | Cite as

Immunomodulatory effect of NSAID in geriatric patients with acute infection: effects of piroxicam on chemokine/cytokine secretion patterns and levels of heat shock proteins. A double-blind randomized controlled trial. (ISRCTN58517443)

  • Ingo Beyer
  • Rose Njemini
  • Ivan Bautmans
  • Christian Demanet
  • Tony Mets
Original Paper

Abstract

Inflammation in older persons is associated with frailty, cachexia, and disability. We hypothesized that NSAID treatment in addition to antibiotics in older patients with acute infection might rapidly reduce inflammatory cytokines and might be of therapeutic potential to improve outcomes. A double-blind controlled trial was conducted in geriatric patients admitted for acute infection. Patients were randomized to receive either 10 mg piroxicam or placebo. Patients ≥70 years with CRP levels >10 mg/L of acute infectious origin were eligible. Twenty-five cyto-/chemokines as well as heat shock proteins Hsp27 (HSPB1) and Hsp70 (HSPA1A) were measured the first 4 days and then weekly until discharge, with a maximum of 3 weeks. Thirty Caucasian patients were included (median age 84.5 years, 67% female, median CRP 87.5 mg/L). In the piroxicam group, IL-6 and IP-10/CXCL10 decreased significantly during the study period. Relationships between cytokines were disrupted in the piroxicam group: for 12 out of 20 cytokines the number of correlations between changes in serum levels was significantly lower compared to placebo. Serum Hsp70 levels decreased significantly in the piroxicam group, but not in the placebo group. Without heat challenge, intracellular levels of Hsp70 in monocytes decreased in both groups, whereas HsP27 in monocytes increased with piroxicam with a significant difference compared to placebo at 3 weeks. Piroxicam in this setting cannot be considered merely as an anti-inflammatory drug, but rather as an immunomodulator. Further studies are needed to establish whether these effects can change functional outcomes in geriatric patients.

Keywords

Infection Inflammation Cytokines/chemokines NSAID Piroxicam 

References

  1. Antonelli A, Rotondi M, Fallahi P, Ferrari SM, Paolicchi A, Romagnani P, Serio M, Ferrannini E (2006) Increase of CXC chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing. Cytokine 34(1–2):32–38PubMedCrossRefGoogle Scholar
  2. Bautmans I, Njemini R, Lambert M, Demanet C, Mets T (2005) Circulating acute phase mediators and skeletal muscle performance in hospitalized geriatric patients. j gerontol 60(3):361–367Google Scholar
  3. Bautmans I, Njemini R, Predom H, Lemper JC, Mets T (2008) Muscle endurance in elderly nursing home residents is related to fatigue perception, mobility, and circulating tumor necrosis factor-alpha, interleukin-6, and heat shock protein 70. J Am Geriatr Soc 56(3):389–396PubMedCrossRefGoogle Scholar
  4. Brameshuber M, Weghuber J, Ruprecht V, Gombos I, Horvath I, Vigh L, Eckerstorfer P, Kiss E, Stockinger H, Schutz GJ (2010) Imaging of mobile long-lived nanoplatforms in the live cell plasma membrane. J Biol Chem 285(53):41765–41771PubMedCrossRefGoogle Scholar
  5. Cho JY (2007) Immunomodulatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) at the clinically available doses. Arch pharm res 30(1):64–74PubMedCrossRefGoogle Scholar
  6. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41PubMedCrossRefGoogle Scholar
  7. Cruse JM, Lewis RE (2010) Cytokines and chemokines. In: Atlas of Immunology, 3rd edn. CRC Press, Boca Raton, FL, pp. 343–381Google Scholar
  8. El Solh A, Pineda L, Bouquin P, Mankowski C (2006) Determinants of short and long term functional recovery after hospitalization for community-acquired pneumonia in the elderly: role of inflammatory markers. BMC Geriatr 6:12PubMedCrossRefGoogle Scholar
  9. Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annual review med 51:245–270CrossRefGoogle Scholar
  10. Ferrucci L, Guralnik JM, Studenski S, Fried LP, Cutler GB Jr, Walston JD (2004) Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older persons: a consensus report. J Am Geriatr Soc 52(4):625–634PubMedCrossRefGoogle Scholar
  11. Ginaldi L, De Martinis M, D’Ostilio A, Marini L, Loreto MF, Martorelli V, Quaglino D (1999) The immune system in the elderly: II. Specific cellular immunity. Immunol Res 20(2):109–115PubMedCrossRefGoogle Scholar
  12. Haynes L, Maue AC (2009) Effects of aging on T cell function. Curr Opin Immunol 21(4):414–417PubMedCrossRefGoogle Scholar
  13. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW (1963) Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function. Jama 185:914–919PubMedCrossRefGoogle Scholar
  14. Kawaguchi M, Kokubu F, Huang SK, Homma T, Odaka M, Watanabe S, Suzuki S, Ieki K, Matsukura S, Kurokawa M, Adachi M (2007) The IL-17F signaling pathway is involved in the induction of IFN-gamma-inducible protein 10 in bronchial epithelial cells. J allergy clin immunol 119(6):1408–1414PubMedCrossRefGoogle Scholar
  15. Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9(3):179–186PubMedCrossRefGoogle Scholar
  16. Lee BS, Chen J, Angelidis C, Jurivich DA, Morimoto RI (1995) Pharmacological modulation of heat shock factor 1 by antiinflammatory drugs results in protection against stress-induced cellular damage. Proc Natl Acad Sci U S A 92(16):7207–7211PubMedCrossRefGoogle Scholar
  17. Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO, Stiles JK (2011) CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine growth factor reviews. doi:10.1016/j.cytogfr.2011.06.001
  18. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435PubMedCrossRefGoogle Scholar
  19. Memis D, Karamanlioglu B, Turan A, Koyuncu O, Pamukcu Z (2004) Effects of lornoxicam on the physiology of severe sepsis. Crit Care 8(6):474–482CrossRefGoogle Scholar
  20. Mets T, Bautmans I, Njemini R, Lambert M, Demanet C (2004) The influence of celecoxib on muscle fatigue resistance and mobility in elderly patients with inflammation. Am J Geriatr Pharmacother 2(4):230–238PubMedCrossRefGoogle Scholar
  21. Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361(9):888–898PubMedCrossRefGoogle Scholar
  22. Morley JE, Thomas DR, Wilson MM (2006) Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 83(4):735–743PubMedGoogle Scholar
  23. Njemini R, Abeele MV, Demanet C, Lambert M, Vandebosch S, Mets T (2002) Age-related decrease in the inducibility of heat-shock protein 70 in human peripheral blood mononuclear cells. J Clin Immunol 22(4):195–205PubMedCrossRefGoogle Scholar
  24. Njemini R, Lambert M, Demanet C, Vanden Abeele M, Vandebosch S, Mets T (2003) The induction of heat shock protein 70 in peripheral mononuclear blood cells in elderly patients: a role for inflammatory markers. Hum Immunol 64(6):575–585PubMedCrossRefGoogle Scholar
  25. Njemini R, Demanet C, Mets T (2004) Inflammatory status as an important determinant of heat shock protein 70 serum concentrations during aging. Biogerontology 5(1):31–38PubMedCrossRefGoogle Scholar
  26. Njemini R, Bautmans I, Lambert M, Demanet C, Mets T (2007a) Heat shock proteins and chemokine/cytokine secretion profile in ageing and inflammation. Mech ageing development 128(7–8):450–454CrossRefGoogle Scholar
  27. Njemini R, Lambert M, Demanet C, Kooijman R, Mets T (2007b) Basal and infection-induced levels of heat shock proteins in human aging. Biogerontology 8(3):353–364PubMedCrossRefGoogle Scholar
  28. Njemini R, Demanet C, Mets T (2008) Aging-related differences in basal heat shock protein 70 levels in lymphocytes are linked to altered frequencies of lymphocyte subsets. Aging cell 7(4):498–505PubMedCrossRefGoogle Scholar
  29. Njemini R, Bautmans I, Onyema OO, Van Puyvelde K, Demanet C, Mets T (2011) Circulating heat shock protein 70 in health, aging and disease. BMC Immunol 12(1):24PubMedCrossRefGoogle Scholar
  30. Okamura M, Takano Y, Hiramatsu N, Hayakawa K, Yao J, Paton AW, Paton JC, Kitamura M (2008) Suppression of cytokine responses by indomethacin in podocytes: a mechanism through induction of unfolded protein response. Am J Physiol Renal Physiol 295(5):F1495–F1503PubMedCrossRefGoogle Scholar
  31. Qu T, Yang H, Walston JD, Fedarko NS, Leng SX (2009) Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. Cytokine 46(3):319–324PubMedCrossRefGoogle Scholar
  32. Rosenstein ED, Kunicka J, Kramer N, Goldstein G (1994) Modification of cytokine production by piroxicam. J Rheumatol 21(5):901–904PubMedGoogle Scholar
  33. Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T, Kita T (2000) Altered Th1/Th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol 120(2):267–273PubMedCrossRefGoogle Scholar
  34. Schaap LA, Pluijm SM, Deeg DJ, Visser M (2006) Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med 119(6):526-e529–526-e517CrossRefGoogle Scholar
  35. Stryer L (1995) Biochemistry, 4th edn. WH Freeman Co, San Francisco, pp 918–919Google Scholar
  36. Teeling JL, Cunningham C, Newman TA, Perry VH (2010) The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: implications for a role of COX-1. Brain Behav Immun 24(3):409–419PubMedCrossRefGoogle Scholar
  37. Tegeder I, Pfeilschifter J, Geisslinger G (2001) Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J 15(12):2057–2072PubMedCrossRefGoogle Scholar
  38. Yeo M, Kwak MS, Kim DK, Chung IS, Moon BS, Song KS, Hahm K-B (2006) The novel acid pump antagonists for anti-secretory actions with their peculiar applications beyond acid suppression. J Clin Biochem Nutri 38(1):1–8CrossRefGoogle Scholar

Copyright information

© Cell Stress Society International 2012

Authors and Affiliations

  • Ingo Beyer
    • 1
    • 2
    • 4
  • Rose Njemini
    • 2
  • Ivan Bautmans
    • 1
    • 2
  • Christian Demanet
    • 3
  • Tony Mets
    • 1
    • 2
  1. 1.Department of GeriatricsUniversitair Ziekenhuis BrusselBrusselsBelgium
  2. 2.Frailty in Aging Research Group (FRIA)Vrije Universiteit Brussel (VUB)BrusselsBelgium
  3. 3.Department of HLA and Molecular HematologyUniversitair Ziekenhuis BrusselBrusselsBelgium
  4. 4.Dienst GeriatrieUZ BrusselBrusselsBelgium

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