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Abstract: Slide Presentations |

PIRFENIDONE MEDIATES DIFFERENTIAL EFFECTS ON LIPOPOLYSACCHARIDE-INDUCED CYTOKINE EXPRESSION IN HUMAN PERIPHERAL MONONUCLEAR CELLS FREE TO VIEW

Roderick Phillips, PhD*; Tony Wang, MD; Lawrence M. Blatt, PhD; Scott Seiwert, PhD
Author and Funding Information

InterMune, Inc., Brisbane, CA


Chest


Chest. 2005;128(4_MeetingAbstracts):169S. doi:10.1378/chest.128.4_MeetingAbstracts.169S-a
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Abstract

PURPOSE:  Idiopathic pulmonary fibrosis (IPF) is a fatal, progressive disorder for which there is no FDA-approved therapy. Although the etiology is unknown, augmented proinflammatory mediator production (such as tumor necrosis factor [TNF]–α and interleukin [IL]-1β), coupled with increased proinflammatory cell recruitment and deposition of extracellular matrix (ECM) proteins, are thought to be crucial steps in disease development. One promising treatment for IPF is pirfenidone (PFD). To support ongoing clinical studies we investigated the biological basis of pirfenidone activity.

METHODS:  Human peripheral blood mononuclear cells (PBMCs; 100,000 cells per well in triplicate) were pretreated with PFD (5 mM to 5 μM) for 1 h and then stimulated with lipopolysaccharide (LPS; 1 μg/mL to 0.01 ng/mL) for 1, 2, 4, 8, or 24 h. Supernatants were then collected and assayed for protein expression using a multiplex cytokine platform (BioRad, Inc.).

RESULTS:  PFD had differential effects on cytokine expression in PBMCs following LPS stimulation. We find that half-maximal inhibition of TNF-α secretion (TNF-α EC50) occurred with between 720 μM and 962 μM PFD, depending on the concentration of LPS. Given that the maximal human serum concentration of PFD is 88 μM following 800 mg TID, these data indicate TNF-α levels would maximally be reduced by 8.6% in patients receiving this regimen. Simultaneous monitoring of 16 other cytokines demonstrated that PFD additionally inhibited expression of GM-CSF, IFN-γ, IL-1β, IL-2, and IL-4, but augmented expression of IL-10, and MCP-1.

CONCLUSION:  The effects of PFD on LPS-induced cytokine expression in PBMCs are likely more complex than initially thought. Pirfenidone reduces expression of TNF-α and therefore may reduce expression of ECM components. Since IL-10 pretreatment in mouse models of liver, lung, and pancreatic fibrosis reduced the severity of fibrosis by down-regulating chronic inflammatory responses, our observation that PFD increases IL-10 expression suggests that PFD may modulate the onset of fibrosis by more than one mechanism.

CLINICAL IMPLICATIONS:  Pirfenidone may prove beneficial for the treatment of IPF; further clinical trials are warranted.

DISCLOSURE:  Roderick Phillips, Shareholder; Employee All authors are employees of InterMune, Inc.

Tuesday, November 1, 2005

10:30 AM - 12:00 PM


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