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Fibroproliferation: A New Therapeutic Target for Idiopathic Pulmonary Fibrosis
Marvin I. Schwarz, Kevin K. Brown

Idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) is a progressive fibroproliferative process characterized by the relentless accumulation of extracellular matrix (ECM) in the lung. The outcome is poor and the median survival is 24 to 36 months following diagnosis. Corticosteroids and immunosuppressive drugs, although still recommended, are generally felt to be ineffective in controlling disease progression and have no apparent impact on survival1. Prior reports, citing up to a 20% response rate to these therapies, were uncontrolled and therefore failed to appreciate the biologic variability of the disease in which there can be prolonged survival (up to 10 years) in 10-20% of patients. More importantly, previous studies failed to differentiate between IPF/UIP and the other idiopathic interstitial pneumonias, such as non-specific interstitial pneumonia (NSIP) or cryptogenic organizing pneumonia (COP), two disorders known to respond to anti-inflammatory therapy2.

The characteristic pathologic feature of IPF/UIP, whether early or late in the disease course, is fibrosis. This fibrosis may or may not be accompanied by chronic inflammatory cell infiltrate, which if present is minimal. Why then, for the past 30 years, has the therapeutic emphasis been placed on anti-inflammatory and immunosuppressive therapies? By the early '50s a response to corticosteroids had been shown in sarcoidosis and berylliosis. Given the lack of distinct histopathologic diagnoses at the time, corticosteroids were then applied to all diffuse lung diseases. Though the results were generally unimpressive, their use continued given anecdotal improvements and the lack of any effective alternative. In the '80s, utilizing bronchoalveolar lavage (BAL), the typical cell profile in IPF/UIP indicated variable numbers of lymphocytes, neutrophils and eosinophils suggesting an acute inflammatory etiology. It is now apparent that the increased numbers of lymphocytes were found primarily in those patients with NSIP and hypersensitivity pneumonitis, while the neutrophils and eosinophils were obtained from areas of end-stage honeycomb lung in which mucostasis occurs and in turn is prone to the accumulation of intraluminal acute inflammatory cells. Therefore, the acute inflammation represents a secondary response rather than a primary initiating event. Unfortunately available animal models did not help and possibly hindered the search for a therapy. There are no animal models that equate to human IPF/UIP. The commonly used bleomycin model, in which interstitial fibroproliferation follows epithelial injury and an acute inflammatory response, does respond to immunosuppressive therapy, but is more applicable to acute lung injury or drug-induced lung disease, not UIP.

Although the initiating event remains unknown, IPF/UIP is a temporally and spatially heterogeneous disease3. This suggests an ongoing intermittent injury, with a dysregulated reparative response. The fibroproliferative features of IPF/UIP are of different ages and consist of combinations of variable amounts of "normal" lung, end-stage honeycomb lung, mature interstitial collagen, and localized interstitial subepithelial areas of fibroblastic proliferation, known as fibroblastic foci. This is in contrast to the other idiopathic interstitial pneumonias (NSIP, COP and acute interstitial pneumonia), in which all sections of affected lung show similar histopathologic features.

A distinctive histopathologic feature of IPF/UIP are the aforementioned fibroblastic foci. They are located directly beneath the alveolar epithelium and may represent a focal area of dysregulated response to epithelial injury4. They are often found at the junction between normal and abnormal lung. Made up primarily of ECM components and fibroblasts, the majority of the fibroblasts stain positively for alpha smooth muscle actin and, therefore, are in fact myofibroblasts. These fibroblasts, under the influence of profibrotic cytokines (e.g. transforming growth factor beta (TGF-beta)) released from either injured epithelial cells, Th2 type lymphocytes or macrophages migrate, proliferate and transform into myofibroblasts and lay down extracellular matrix. Myofibroblasts not only produce collagen, but like their counterparts, the smooth muscle cells, have contractile properties which can distort the lung architecture5. We have shown that in contrast to the amount of collagen or inflammatory cell infiltration, the only histologic feature of UIP which determines survival is the number of fibroblastic foci present6. The higher the number of fibroblastic foci, the shorter the survival. It is then not unreasonable to suggest that it is the fibroblastic foci and their myofibroblasts which drive the fibrotic process and should be the therapeutic target for new interventions in this uniformly fatal disease.

One of the most potent pro-proliferative cytokines is TGF-b1 which is readily identified within the fibroblastic foci and the bronchoalveolar lavagates of IPF/UIP subjects7. TGF-b1 is a Th2 cytokine which supports fibroblast migration, proliferation, transformation into myofibroblasts and collagen production, as well as inhibiting myofibroblast apoptosis8. It is involved in the release of connective tissue growth factor (CTGF) another potent pro-fibrotic cytokine. Other pro-proliferative proteins known to be upregulated in IPF/UIP include tumor necrosis factor a (TNFa), endothelin 1 (ET-1), angiotensin-2 and interleukin 4 (IL-4). One naturally occurring anti-proliferative cytokine is interferon gamma (IFNg). IFNg, a Th1 cytokine, IFNg antagonizes many of the fibroproliferative properties of TGF-b1. Based on this, a promising but limited phase 2 trial was performed which indicated improved pulmonary function after one year of three times weekly subcutaneous IFNg9. A large phase 3 trial in the USA involving over 300 patients is now nearing completion.

Other therapeutic trials in IPF/UIP are being considered. Increased amounts of ET-1 are present in the lungs of IPF/IPF patients. ET-1 in addition to its potent pulmonary vasoactive properties, is a potent myofibroblast inducer16. ET-1 receptor antagonists, now available for the treatment of primary pulmonary hypertension, should also be tested in IPF/UIP and possibly other fibrotic lung diseases such as scleroderma. Antibodies against or soluble receptors for TNFa which have been approved for the treatment of rheumatoid arthritis and inflammatory bowel disease could also be applied to IPF/UIP. Pirfenidone a compound which reduced fibrosis in a bleomycin model due to the down regulation of TGF-b1 gene expression and had encouraging results in an open label human study is currently being tested in Japan11. Other potential anti-TGF-b1 therapies include antibodies, soluble receptors, decorin and SMAD-712,13. Decorin is a naturally occurring ECM molecule which effectively blocks all actions of TGF-b1. SMAD-7 is an intracellular signaling molecule which inhibits the transmission of the TGF-b1 signal from the surface of the cell to its nucleus.

Therapies such as these are directed at controlling the primary pathologic event in IPF/UIP, namely the dysregulated fibroproliferative response. It is only when this response is controlled will the production of collagen be checked, quality of life improved and extended survival be realized for patients with IPF/UIP.


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© 2011 PNEUMON Magazine, Hellenic Bronchologic Society.
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