Pirfenidone suppresses tumor necrosis factor-α, enhances interleukin-10 and protects mice from endotoxic shock

Oku, Hiromasa; Nakazato, Hitoshi; Horikawa, Tsuyoshi; Tsuruta, Yuji; Suzuki, Ryuji

doi:10.1016/s0014-2999(02)01757-0

Cited by 143 publications

(96 citation statements)

References 39 publications

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“…Mice received subcutaneous injections of pirfenidone (Shionogi, Tokyo, Japan) (125, 250, or 500 mg/kg daily versus saline as vehicle) from Days 26 to 31 in the short exposure model (Figure 1) (14,15,22). In the repeated exposure model, mice received subcutaneous injections of pirfenidone (500 mg/kg/d) from Days 26 to 59.…”

Section: Administration Of Pirfenidonementioning

confidence: 99%

Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Hirano

Kanehiro

Ono

et al. 2006

Am J Respir Cell Mol Biol

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We investigated the therapeutic potential of a newly developed antifibrotic agent, pirfenidone, to regulate airway remodeling and the development of allergic airway inflammation and airway hyperresponsiveness after chronic allergen challenge. Administration of pirfenidone after sensitization but during the period of ovalbumin challenge significantly prevented the development of airway hyperresponsiveness and prevented eosinophil and lymphocyte accumulation in the airways. IL-4, IL-5, and IL-13 levels in bronchoalveolar lavage fluid and ovalbumin-specific serum IgE antibody levels were also significantly reduced. Treatment with pirfenidone significantly reduced transforming growth factor-␤1 and platelet-derived growth factor levels in bronchoalveolar lavage fluid. Pirfenidone reduced the expression of transforming growth factor-␤1, the development of goblet cell hyperplasia and subepithelial collagenization, and the increases in contractile elements in the lung. These data indicate that pirfenidone may play an important role in the treatment of asthma and has the potential reduce or prevent airway remodeling.

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Section: Administration Of Pirfenidonementioning

confidence: 99%

Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Hirano

Kanehiro

Ono

et al. 2006

Am J Respir Cell Mol Biol

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“…15,16 In animal models and cell culture studies, pirfenidone also reduces TNF-␣ production. 17,18 We have found that oral pirfenidone administered to db/db mice after the onset of established diabetic kidney disease was effective in reducing glomerulosclerosis. 19 In addition, in an open-label clinical study in patients with advanced and treatment-refractory focal segmental glomerulosclerosis (FSGS), there was a 25% reduction in the rate of estimated GFR (eGFR) decline in patients on pirfenidone as compared with the rate of decline before pirfenidone.…”

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confidence: 99%

Pirfenidone for Diabetic Nephropathy

Sharma¹,

Ix²,

Mathew³

et al. 2011

Journal of the American Society of Nephrology

269

148

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Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebocontrolled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m 2 ). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (ϩ3.3 Ϯ 8.5 ml/min per 1.73 m 2 ) whereas the mean eGFR decreased in the placebo group (Ϫ2.2 Ϯ 4.8 ml/min per 1.73 m 2 ; P ϭ 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (Ϫ1.9 Ϯ 6.7 ml/min per 1.73 m 2 ). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P ϭ 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

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“…In this study, mice challenged with high doses of LPS resulted in a syndrome resembling septic shock in humans (20,21). We investigated the protective effect of apoptotic cells, demonstrating that i.v.…”

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confidence: 99%

Apoptotic Cells Protect Mice against Lipopolysaccharide-Induced Shock

Ren

Xie

Jiang

et al. 2008

The Journal of Immunology

135

128

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LPS is a main causative agent of septic shock. There is a lack of effective therapies. In vitro studies have shown that uptake of apoptotic cells actively inhibits the secretion by activated macrophages (Mφ) of proinflammatory mediators such as TNF-α and that such uptake increases the antiinflammatory and immunosuppressive cytokine TGF-β. We therefore investigated the protective effect of apoptotic cells against LPS-induced endotoxic shock in mice. The current report is the first study to demonstrate that administration of apoptotic cells can protect mice from LPS-induced death, even when apoptotic cells were administered 24 h after LPS challenge. The beneficial effects of administration of apoptotic cells included 1) reduced circulating proinflammatory cytokines, 2) suppression of polymorphonuclear neutrophil infiltration in target organs, and 3) decreased serum LPS levels. LPS can quickly bind to apoptotic cells and these LPS-coated apoptotic cells can be recognized and cleared by Mφ in a CD14/thrombospondin/vitronectin receptor-dependent manner, accompanied with suppression of TNF-α and enhancement of IL-10 expression by LPS-activated Mφ. Apoptotic cells may therefore have therapeutic potential for the treatment of septic shock.

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Pirfenidone suppresses tumor necrosis factor-α, enhances interleukin-10 and protects mice from endotoxic shock

Cited by 143 publications

References 39 publications

Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge

Pirfenidone for Diabetic Nephropathy

Apoptotic Cells Protect Mice against Lipopolysaccharide-Induced Shock

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