Pulmonary fibrosis complicates a heterogeneous group of disorders that are driven by chronic inflammation or repeated epithelial injury and involve regions of the lung varying from mainly airways to almost exclusively the lung parenchyma. More broadly, fibrosis is a final common pathway in many forms of chronic disease, affecting a range of tissues and leading to organ scarring and failure. Although fibrosis in various forms affects millions of patients in the United States, there is a paucity of adequate treatment options. Thus, there is a need to translate an understanding of basic disease mechanisms to the more pragmatic challenges associated with the clinical development of novel therapeutics. The most therapeutically challenging of these diseases in the lung is idiopathic pulmonary fibrosis (IPF). Although there have been many advances in clarifying the diagnosis and prognosis of IPF over the last decades, no medical therapy has significantly improved survival or halted the relentless progression of fibrogenesis (63
). The failure of antiinflammatory agents to favorably affect the course of IPF, coupled with the elucidation of defects that primarily involve AECs being associated with familial IPF, has turned attention to the pathobiology of epithelial–mesenchymal interactions in this disease. This has led to a number of clinical trials involving agents that, on the basis of preclinical studies in mouse models, were thought to focus on signaling pathways directly or indirectly involved in fibrogenesis. These include pirfenidone, etanercept, interferons, and, most recently, imatinib mesylate and bosentan. Unfortunately, none of these agents has demonstrated an unequivocal clinical benefit.
What lessons can one derive from the recent therapeutic failures? And what is needed in the field to inform and promote new clinical trials that better address critical elements of the pathobiology? Members of the workshop discussed key obstacles in translating basic studies to the clinical arena and attempted to identify several short- and more long-term advances that would increase the likelihood of developing promising therapies. Although much of the discussion was directed toward IPF, many of the principles elucidated are relevant to other chronic lung diseases. The group identified four major areas for high-impact discovery.
Continued Basic Studies that Elucidate Key Drivers of Pulmonary Fibrosis in Humans
One lesson from recent clinical trials is that a molecular understanding of what drives the relentless fibrosis in IPF is unclear. A more complete understanding of the signaling pathways underlying fibrogenesis should result in new therapeutic targets more specifically directed toward fibrosis. In addition, because completely inhibiting a specific pathway may have adverse unintended consequences in the same or another cell type, more detailed knowledge of specific downstream targets and molecular interactions will be important.
New Animal Models that More Closely Resemble the Pathobiology of Progressive Pulmonary Fibrosis
A careful consideration of the model(s) in which preclinical data are obtained is important. Despite its limitations, the bleomycin-induced lung injury model remains the most widely used and best characterized model for studying potential antifibrotic agents. An important limitation of the bleomycin model is that fibrosis is highly dependent on inflammation induced by epithelial injury, whereas IPF has not proven responsive to antiinflammatory therapeutics. Inhibition of fibrosis in the bleomycin model by drugs given early after injury does not predict clinical responses. Although the bleomycin lung injury model has severe limitations, it has provided valuable insights into potential pathways involved in the pathogenesis of fibrosis, including molecular markers that reflect disease mechanisms impairing epithelial cell health and promoting fibrogenesis and that can reliably serve as interim indicators of a therapeutic response.
A major barrier to the development of therapeutics for fibrosis is the lack of interim indicators that reliably reflect drug effects on mechanisms of disease. Generating basic research tools and model systems to evaluate the relevance of target pathways to human disease and developing biomarkers to monitor the effectiveness of therapeutic intervention in clinical trials will greatly facilitate the development of novel therapies. Toward this end, understanding how molecular mechanisms regulating fibrotic disease in animal models overlap with human disease can lead to the identification of new biomarkers.
Personalized medicine refers to therapy based on the elucidation of family history, environmental exposures, distinct clinical features and outcomes, biochemical phenotypes, and pathological characteristics that together identify dominant signaling pathways affecting the progression and outcome of disease in an individual patient. Chronic illness represents over 75% of medical care in the United States. These diseases are complex disorders that result from a combination of genetic factors and environmental exposures. We tend to label them as distinct diseases; however, the diseases are more appropriately labeled syndromes to indicate involvement of a variety of molecular pathways and clinical subphenotypes within each category. Moreover, the diseases themselves often have overlapping genetic and environmental components with common pathologic manifestations. The goal of personalized medicine is to match specific aberrant molecular pathways with clinical subphenotypes and develop specific therapy for each individual patient.
The overlap of COPD and IPF represents the blurring of disease categories based upon common environmental exposures and pathologic phenotypes. At first glance, COPD and IPF appear to be diametrically opposed. Emphysema is a result of inflammation induced by cigarette smoke and proteolytic destruction of elastin and other ECM components, whereas IPF is not necessarily inflammation dependent and is characterized by relentless extracellular matrix deposition. However, around two thirds of patients with IPF are cigarette smokers. Moreover, epithelial cell apoptosis, matrix metalloproteinase activation, and net collagen accumulation are characteristic of COPD and IPF.
Even though the prognosis of IPF is generally poor, there is abundant evidence that there is substantial heterogeneity in the outcomes even within a biopsy-proven patient population. Cell plasticity may play a role with phenotypic switching, which can account for clinically distinct manifestations. Certain putative biomarkers of disease activity are elevated in some but not other patients with IPF. To effectively bring new therapeutic targets to the clinical arena, it will be crucial to identify at the outset the set of patients most likely to respond to a particular treatment. It may also be the case that the activity of one or only a few signaling pathways dominates disease progression in all patients, but there is little evidence to support this possibility.
- Development of animal models of lung fibrosis that better reflect human disease. Elements of an animal model(s) that would potentially facilitate the identification of novel drug targets need to include:
- Fibrosis must be persistent, ideally unrelenting, and lead to increased mortality due to fibrosis.
- The model should include AEC injury.
- Inducible AEC-specific transgenic models that manipulate specific genes that have been implicated in the pathobiology of usual interstitial pneumonia should be developed. Pathways to be considered should include telomerase, surfactant proteins A and C, components of vesicle trafficking, ER stress and unfolded protein response pathways, genes downstream of TGF-β1 activation, and Wnt signaling pathways.
- In addition to targeting AECs, models that genetically manipulate genes expressed by myofibroblasts also offer the potential to identify novel targets. These should also preferably be inducible systems.
- Signaling pathways found to be critical in animal models should be tested directly in epithelial cells and fibroblasts isolated from patients or in lung tissues from patients to validate their role in human disease. Most of the transcriptional and biochemical profiling of fibrotic patients has been at the level of whole lungs. This will likely not provide sufficient resolution to identify critical epithelial or fibroblastic subphenotypes or signaling pathways within a patient population or applicable to a single patient.
- Develop a biomarker of fibrogenic activity that is detectable by noninvasive imaging to facilitate monitoring of therapeutic response. In addition to development of better serum, urine, or bronchoalveolar lavage (BAL) markers of disease activity, there is much promise, and also challenge, in the development of functional imaging of fibrogenesis in lungs. Other than detection of the enhanced metabolic activity of lung tumors, no functional imaging is in clinical use in the lung. The development of such technology would greatly enhance the early quantification of functional impairment and the ability to monitor therapeutic candidates in pulmonary fibrosis.
- Emphasize subgroup analysis of promising biomarkers (from blood, BAL, or urine) to elucidate connections between biochemical markers and lung disease progression in patient groups or individuals. There is no biomarker that tracks disease activity with enough variation to be useful in phenotyping subpopulations or predicting therapeutic response. Consider gender differences and reproductive history in the evaluation of response to lung injury and response to treatment.
- Determine if there are both common and distinct patterns of epigenetic or genomic profiling of epithelial cells and fibroblasts isolated from, or assessed in situ in, fibrotic patients. If so, coordinate testing the correlation of such patterns with parameters of clinical and pathological disease progression.