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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 107-108, (2004)
© 2004 American Thoracic Society

Editorial

Interferon-{gamma} 1b in Idiopathic Pulmonary Fibrosis

What We Know and What Must We Learn

James H. Dauber, M.D., Kevin F. Gibson, M.D. and Naftali Kaminski, M.D.

Division of Pulmonary, Allergy, and Critical Care Medicine University of Pittsburgh Pittsburgh, Pennsylvania

Rationales for the trials of interferon-{gamma} in idiopathic pulmonary fibrosis are based on sound biological knowledge and promising initial observations (1, 2). However, after a large prospective study in which 162 patients received interferon-{gamma}, the actual effect and its mechanism are still debated. The study by Streiter and coworkers in this issue of the Journal (pp. 133–140), which aimed to understand the effects of interferon-{gamma}, revealed that its administration in idiopathic pulmonary fibrosis did not lead to significant changes in expression of genes hypothesized to increase or decrease connective tissue in the idiopathic pulmonary fibrosis lung (3). Only the cytokine CXCL11/ITAC was overexpressed in bronchoalveolar fluid and serum. Technical issues may explain some of the unexpected results. First is the sampling error of transbronchial lung biopsy. Because biopsies were taken blindly in a heterogeneous disease, gene expression may not be the same in all specimens. Second, quantifying protein in bronchoalveolar lavage fluid is notoriously difficult and the lavage procedure may lead to influx of proteins from blood that falsely elevate their concentrations in the fluid. Third, the potential survival benefit attributed to interferon-{gamma} did not become apparent until at least one year of therapy (4). Changes in gene expression measured after one year may have been more impressive, but this is unlikely.

A more conceivable explanation is that this study confirmed the reality that interferon-{gamma} failed to halt progression of disease in patients with idiopathic pulmonary fibrosis treated for up to 56 months (4). The study of Streiter and coworkers is important, though, because it supports the notion that if interferon-{gamma} is beneficial in idiopathic pulmonary fibrosis, it probably is not through a presumed effect on transforming growth factor ß but instead though an alternative pathway. Intuitively, we think to see an impact on remodeling in idiopathic pulmonary fibrosis there should be drastic changes in the expression of genes that regulate extracellular matrix generation and degradation. Nonetheless, the results provide a mechanistic mirror to the clinical study by Raghu and coworkers (4). Patients in that large clinical trial probably did not have improvement in physiological parameters after one year of therapy because there was no significant molecular change in the lung's fibrotic environment at 6 months, as Streiter and coworkers accurately observed. The factors underlying the potential benefit of interferon-{gamma} on survival still need to be elucidated. An elevated concentration of CXCL11/ITAC in both serum and bronchoalveolar fluid is a convincing result that may shed light on the mechanism for increased survival with chronic administration of interferon-{gamma}.

Is CXCL11/ITAC important in the pathogenesis of idiopathic pulmonary fibrosis, or in the response of patients to interferon-{gamma}? The authors make a compelling argument that CXCL11/ITAC is an agent through which interferon-{gamma} exerts its beneficial effect on survival. Given its demonstrated antimicrobial effect, their explanation is plausible. One must remember, however, that the benefit in survival does not have to be mediated by antimicrobial activity alone. Instead, CXCL11/ITAC may play a completely different role. Recently, changes in vascular phenotypes in idiopathic pulmonary fibrosis have gained attention. Abnormal vasculature in the fibrotic lung may contribute to pathogenesis through shunt formation or by a direct effect on fibrotic tissue. It is not clear in idiopathic pulmonary fibrosis whether new vessel formation is favored over inhibition of angiogenesis. Recent data from microarray analysis of human lungs suggested an antiangiogenic milieu (5, 6) in idiopathic pulmonary fibrosis, whereas in animals, bleomycin-induced fibrosis is inhibited by the angiostatic chemokine, IP10/CXCL10 (7) as well as by the pro-angiogenic drug tetrathiomolybdate (8). Ebina and coworkers demonstrated regional diversity in the distribution of blood vessels with a lack of CD34-positive vessels within fibroblast foci but an increase within capillary walls (9). If this is true, an anti-angiogenic effect of CXCL11/ITAC would be detrimental, which is consistent with Kao and colleagues (10), who suggested that CXCL11/ITAC was involved in heart transplant rejection. Clearly these observations open a whole field for investigation.

Idiopathic pulmonary fibrosis is often thought of as a disease with uniformly poor survival, but survival varies widely. Some patients die within one year of diagnosis, whereas others live longer than six years. The reasons for differences in survival remain unknown, but current research suggests that the disease involves more than dysregulation of interferon-{gamma}–inducible genes. Other groups of potentially important genes may (1) control epithelial cell apoptosis, which enhances programmed cell death; (2) produce growth factors, which may attempt to repair the injury to the epithelium but also stimulate the growth of fibroblasts; (3) reduce the turnover of matrix by inducing tissue inhibitors of metaloprotienases; (4) induce matrix metalloproteases with specific effects relevant to promotion of local fibrotic environment; (5) recruit and maintain abnormal fibroblast phenotypes such as the myofibroblast, which is metabolically active and resistant to apoptosis; (6) produce an imbalance of TH1 and TH2 cytokines; and (7) regulate the balance of angiogenesis and angiostasis in the lung (11, 12).

The study by Streiter and coworkers is welcome not only because of its results but also because it is an example of how we should strive to identify effects of a therapeutic intervention on the target (lung) and surrogate tissues (bronchoalveolar fluid, peripheral blood). Since there is no good animal model for idiopathic pulmonary fibrosis, descriptive data obtained from well characterized human subjects may serve to generate mechanistic hypotheses. With current technologies, such a strategy should be inherent to the design of drug studies because it may provide insight into the "real life" biological mechanisms that explain the effect or lack thereof for a therapeutic intervention. The authors selected genes hypothesized to play a role in idiopathic pulmonary fibrosis, but only one out of 19 was significantly changed after administration of interferon-{gamma}. This should serve as a reminder of how little we actually know about the pathogenesis, which then leads to shortsighted hypotheses. Identifying all the genes affected by interferon-{gamma} in this patient group would likely have been more informative. New microarray technologies that allow simultaneous profiling of the expression of all genes in the human genome and high fidelity profiling technologies that allow combinatorial analysis of multiple proteins simultaneously should elucidate the effects of drugs in an accurate and unbiased fashion. In multiple sclerosis there is a gene expression signature diagnostic of disease in peripheral blood monocytes (13). More importantly, a set of genes induced by interferon-ß was identified by microarrays (14). Such analyses have become easier and require less mRNA, while providing good sequence and annotation information. Analytical methods have also increased in number and effectiveness. Thus, the results of Streiter and coworkers reinforce our conviction that in human diseases where multiple pathways interact and where little is known about the actual disease process, screening for changes in gene expression of the whole genome will provide us with a global and unbiased profile of the response to treatment as well as with novel markers and targets for therapeutic interventions.

FOOTNOTES

Conflict of Interest Statement: J.H.D. has attended three advisory board meetings in the last three years for Intermune, Inc. with a total compensation of $6,000 and has lectured for Intermune, Inc. during the last three years with a total compensation of $14,000; K.F.G does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

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