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Rebuttal from Dr. Strieter

Department of Medicine, Division of Pulmonary and Critical Care Medicine and Department of Pathology and Laboratory Medicine, University of California, Los Angeles School of Medicine, Los Angeles, California

Dr. Gauldie's argument would be compelling if the histopathology of UIP (1) represented the beginning, middle, and end stages of the pathogenesis of idiopathic pulmonary fibrosis. Moreover, one could buy this concept if UIP was truly a disease and not the end stage of a process. However, none of these concepts are true. There is now evidence that UIP likely evolves from NSIP, which is characterized by the presence of varying degrees of chronic inflammation and fibrosis (1, 2). Therefore, chronic inflammation can be perceived to be a major component of the pathogenesis of NSIPNSIP-FUIP.

He argues that because antiinflammatory agents are clinically ineffective in the treatment of idiopathic pulmonary fibrosis, inflammation is not involved in the pathogenesis of idiopathic pulmonary fibrosis. Although I agree that conventional antiinflammatory/immunosuppressive agents lack efficacy in the treatment of end-stage pulmonary fibrosis, these agents demonstrate efficacy in the treatment of NSIP, which represents the early stage of the development of NSIP-F and eventually UIP. Unfortunately, the presence of pulmonary fibrosis is more related to the progression of the process; therefore, one can appreciate why antiinflammatory and/or immunosuppressive agents would be less efficacious for the treatment of UIP. This scenario is analogous to why the treatment response and prognosis of stage IV lung cancer is poor compared with that of stage I lung cancer.

Gauldie argues that in idiopathic pulmonary fibrosis, the normal physiologic response is diverted with retention of altered mesenchymal cell phenotype through avoidance of apoptosis with continued and dysregulated fibrogenesis. This explanation would be extremely feasible if we simply looked at UIP in isolation. However, recent evidence for histopathologic variability in idiopathic interstitial pneumonias and the differences in age of patients with primarily NSIP versus UIP (2) supports the notion that chronic inflammation with repeated/persistent episodes of injury is a driving force for the pathogenesis of the fibrogenic process that leads to NSIPNSIP-FUIP. An imbalance of the ratio of expression of Th1:Th2 cytokines polarizes chronic inflammation (3, 4). The repeated and/or persistent episodes of injury induce a switch from an initial Th1 to a response dominated by Th2 cytokines. This response promotes dysregulated repair with persistent chronic inflammation, fibrogenesis, and end-stage fibrosis analogous to UIP.

REFERENCES

1. Katzenstein AL, Myers JD. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1995; 157(4 Pt 1):1301–1305.[Free Full Text]
2. Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, Jain A, Strawderman RL, Flint A, Lynch JP, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001;164:1722–1727.[Abstract/Free Full Text]
3. Infante-Duarte C, Kamradt T. Th1/Th2 balance in infection. Springer Semin Immunopathol 1999;21:317–338.[Medline]
4. Shurin MR, Lu L, Kalinski P, Stewart-Akers AM, Lotze MT. Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol 1999;21:339–359.[Medline]

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