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(Chest. 2004;125:2365.)
© 2004 American College of Chest Physicians

Statin, Inflammation, and Sepsis

Ken-ichiro Inoue, MD; Hirohisa Takano, MD, PhD; Rie Yanagisawa, PhD; Miho Sakurai, PhD and Toshikazu Yoshikawa, MD, PhD

National Institute for Environmental Studies, Tsukuba, Japan

Correspondence to: Ken-ichiro Inoue, MD, Inhalation Toxicology Research Team, and Pathophysiology Research Team, National Institute for Environmental Studies, 16–2 Onogawa, Tsukuba, 305-8506; e-mail: inoue.kenichirou{at}nies.go.jp

To the Editor:

We read with great interest the recent hypothesis by Almog (August 2003).1 He hypothesized that statins may have a strong anti-inflammatory effect against sepsis and its related diseases. Although the mechanisms of the anti-inflammatory and immunomodulatory properties of statins have not been fully clarified, some in vitro studies23 have reported that statins increased the activity of one transcriptional factor, peroxisome proliferator-activated receptor (PPAR)-{gamma} and decreased the transactivation of nuclear factor (NF)-{kappa}B. Although statins are not ligands of PPARs,4 their anti-inflammatory effects may be explained, at least partly, by the activation of PPARs with the inhibition of NF-{kappa}B.

To date, PPAR agonists have been recognized to have anti-inflammatory effects in in vitro and in vivo studies. Among them, the ligands of PPAR-{gamma} have suppressed several types of inflammatory animal models such as colitis,5 rheumatoid arthritis,6 and multiple sclerosis.7 However, PPAR-{gamma} activators do not ameliorate every inflammatory condition. For example, Thieringer et al8 demonstrated that treatment with thiazolidinedione, one of the PPAR-{gamma} ligands, does not suppress the increased circulatory proinflammatory cytokines in db/db mice challenged with IV lipopolysaccharide (LPS), suggesting that the activation of PPAR-{gamma} might not be useful for the treatment of sepsis.

Recently, we have examined the effect of the endogenous PPAR-{gamma} agonist 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PG J2) on acute lung injury induced by LPS in mice.9 We treated ICR mice with 15d-PG J2 (10 µg/kg, 100 µg/kg, or 1 mg/kg) before intratracheal challenge with LPS (125 µg/kg). Unexpectedly, 15d-PG J2, at a dose of 1 mg/kg, did not ameliorate the neutrophilic lung inflammation and pulmonary edema induced by LPS, but, rather, enhanced them. The enhancement was concomitant with the increased lung expression of interleukin-1ß, macrophage inflammatory protein-1{alpha}, and macrophage chemoattractant protein-1. Interestingly, 15d-PG J2 increased the nuclear protein expression of PPAR-{gamma} and inhibited the nuclear localization of NF-{kappa}B related to LPS in murine lungs. In the study, we concluded that 15d-PG J2 may not be useful but may be potentially harmful as a therapeutic option for acute lung injury related to LPS. Therefore, evidence from in vivo studies above the anti-inflammatory effects of statins on sepsis is needed before statins can be used as a therapeutic option in the clinical setting.

References

  1. Almog, Y (2003) Statins, inflammation, and sepsis: hypothesis. Chest 124,740-743[Abstract/Free Full Text]
  2. Mulhaupt, F, Matter, CM, Kwak, BR, et al Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells. Cardiovasc Res 2003;59,755-766[Abstract/Free Full Text]
  3. Zelvyte, I, Dominaitiene, R, Crisby, M, et al Modulation of inflammatory mediators and PPAR{gamma} and NF{kappa}B expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res 2002;45,147-154[CrossRef][ISI][Medline]
  4. Inoue, I, Itoh, F, Aoyagi, S, et al Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NF{kappa}B. Biochem Biophys Res Commun 2002;290,131-139[CrossRef][ISI][Medline]
  5. Su, CG, Wen, X, Bailey, ST, et al A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest 1999;104,383-389[ISI][Medline]
  6. Kawahito, Y, Kondo, M, Tsubouchi, Y, et al 15-deoxy-delta-(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest 2000;106,189-197[ISI][Medline]
  7. Diab, A, Deng, C, Smith, JD, et al Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J Immunol 2002;168,2508-2515[Abstract/Free Full Text]
  8. Thieringer, R, Fenyk-Melody, JE, Le Grand, CB, et al Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-{alpha} responses of macrophages to lipopolysaccharide in vitro or in vivo. J Immunol 2000;164,1046-1054[Abstract/Free Full Text]
  9. Inoue, K, Takano, H, Yanagisawa, R, et al Effect of 15-deoxy-{Delta}12,14-prostaglandin J2 on acute lung in jury induced by lipopolysaccharide in mice. Eur J Pharmacol 2003;481,261-269[CrossRef][Medline]

Statin, Inflammation, and Sepsis

Yaniv Almog, MD

Ben Gurion University, Beer-Sheva, Israel

Correspondence to: Yaniv Almog, MD, PO Box 653, Beer-Sheva 84105, Israel; e-mail: almogya{at}bgumail.bgu.ac.il

To the Editor:

I agree that the mechanisms of the anti-inflammatory and immunomodulatory effects of statins have not been fully elucidated. In fact, more than one pathway may be involved, including nuclear factor-kB.1 I also agree that additional studies are required to determine the precise role of statins as anti-inflammatory agents in patients with a wide variety of conditions. Finally, I am sure that the authors noticed that we did not suggest a therapeutic effect for statins in patients with severe sepsis but rather a preventive one.2

References

  1. Blanco-Colio, LM, Tunon, J, Martin-Ventura, JL, et al Anti-inflammatory and immunomodulatory effects of statins. Kidney Int 2003;63,12-23[CrossRef][ISI][Medline]
  2. Almog, Y Statins, inflammation, and sepsis: hypothesis. Chest 2003;124,740-743




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