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Communications to the Editor |

Statin, Inflammation, and SepsisStatin, Inflammation, and Sepsis FREE TO VIEW

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

Affiliations: National Institute for Environmental Studies, Tsukuba, Japan,  Ben Gurion University, Beer-Sheva, Israel

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@nies.go.jp



Chest. 2004;125(6):2365. doi:10.1378/chest.125.6.2365
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To the Editor:

We read with great interest the recent hypothesis by Almog (August 2003).1He 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 studies3 have reported that statins increased the activity of one transcriptional factor, peroxisome proliferator-activated receptor (PPAR)-γ and decreased the transactivation of nuclear factor (NF)-κB. 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-κB.

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-γ have suppressed several types of inflammatory animal models such as colitis,5rheumatoid arthritis,6and multiple sclerosis.7However, PPAR-γ activators do not ameliorate every inflammatory condition. For example, Thieringer et al8 demonstrated that treatment with thiazolidinedione, one of the PPAR-γ ligands, does not suppress the increased circulatory proinflammatory cytokines in db/db mice challenged with IV lipopolysaccharide (LPS), suggesting that the activation of PPAR-γ might not be useful for the treatment of sepsis.

Recently, we have examined the effect of the endogenous PPAR-γ agonist 15-deoxy-Δ12,14-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-1β, macrophage inflammatory protein-1α, and macrophage chemoattractant protein-1. Interestingly, 15d-PG J2 increased the nuclear protein expression of PPAR-γ and inhibited the nuclear localization of NF-κB 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.

Almog, Y (2003) Statins, inflammation, and sepsis: hypothesis.Chest124,740-743. [CrossRef] [PubMed]
 
Mulhaupt, F, Matter, CM, Kwak, BR, et al Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.Cardiovasc Res2003;59,755-766. [CrossRef] [PubMed]
 
Zelvyte, I, Dominaitiene, R, Crisby, M, et al Modulation of inflammatory mediators and PPARγ and NFκB expression by pravastatin in response to lipoproteins in human monocytesin vitro.Pharmacol Res2002;45,147-154. [CrossRef] [PubMed]
 
Inoue, I, Itoh, F, Aoyagi, S, et al Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFκB.Biochem Biophys Res Commun2002;290,131-139. [CrossRef] [PubMed]
 
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 Invest1999;104,383-389. [CrossRef] [PubMed]
 
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 Invest2000;106,189-197. [CrossRef] [PubMed]
 
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 Immunol2002;168,2508-2515. [PubMed]
 
Thieringer, R, Fenyk-Melody, JE, Le Grand, CB, et al Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-α responses of macrophages to lipopolysaccharidein vitroorin vivo.J Immunol2000;164,1046-1054. [PubMed]
 
Inoue, K, Takano, H, Yanagisawa, R, et al Effect of 15-deoxy-Δ12,14-prostaglandin J2on acute lung in jury induced by lipopolysaccharide in mice.Eur J Pharmacol2003;481,261-269. [CrossRef] [PubMed]
 

Statin, Inflammation, and Sepsis

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.1I 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
Blanco-Colio, LM, Tunon, J, Martin-Ventura, JL, et al Anti-inflammatory and immunomodulatory effects of statins.Kidney Int2003;63,12-23. [CrossRef] [PubMed]
 
Almog, Y Statins, inflammation, and sepsis: hypothesis.Chest2003;124,740-743. [CrossRef] [PubMed]
 

Figures

Tables

References

Almog, Y (2003) Statins, inflammation, and sepsis: hypothesis.Chest124,740-743. [CrossRef] [PubMed]
 
Mulhaupt, F, Matter, CM, Kwak, BR, et al Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells.Cardiovasc Res2003;59,755-766. [CrossRef] [PubMed]
 
Zelvyte, I, Dominaitiene, R, Crisby, M, et al Modulation of inflammatory mediators and PPARγ and NFκB expression by pravastatin in response to lipoproteins in human monocytesin vitro.Pharmacol Res2002;45,147-154. [CrossRef] [PubMed]
 
Inoue, I, Itoh, F, Aoyagi, S, et al Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFκB.Biochem Biophys Res Commun2002;290,131-139. [CrossRef] [PubMed]
 
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 Invest1999;104,383-389. [CrossRef] [PubMed]
 
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 Invest2000;106,189-197. [CrossRef] [PubMed]
 
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 Immunol2002;168,2508-2515. [PubMed]
 
Thieringer, R, Fenyk-Melody, JE, Le Grand, CB, et al Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-α responses of macrophages to lipopolysaccharidein vitroorin vivo.J Immunol2000;164,1046-1054. [PubMed]
 
Inoue, K, Takano, H, Yanagisawa, R, et al Effect of 15-deoxy-Δ12,14-prostaglandin J2on acute lung in jury induced by lipopolysaccharide in mice.Eur J Pharmacol2003;481,261-269. [CrossRef] [PubMed]
 
Blanco-Colio, LM, Tunon, J, Martin-Ventura, JL, et al Anti-inflammatory and immunomodulatory effects of statins.Kidney Int2003;63,12-23. [CrossRef] [PubMed]
 
Almog, Y Statins, inflammation, and sepsis: hypothesis.Chest2003;124,740-743. [CrossRef] [PubMed]
 
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