PROJECTS UNDERWAY AS OF 2011
The Regulation and Pattern of the DNA Methylome in Pulmonary Fibrosis - Steven Huang, M.D.
One of the key features of idiopathic pulmonary fibrosis (IPF) is the activation of lung fibroblasts, which are the main effector cells responsible for the excessive scarring in the lung. The activation of these cells is associated with increased expression of profibrotic genes and diminished expression of antifibrotic genes. We and others have identified DNA methylation as a critical mechanism responsible for this dysregulated gene expression. We will study how patterns of DNA methylation change in experimental mouse models of fibrosis, and study how prostaglandin E2, an important antifibrotic mediator, may regulate the DNA methylation machinery. This understanding could lead to the opportunity for prostaglandin E2 and DNA methylation inhibitors, which are already in clinical trials for cancer, as potential future therapy for IPF.
Semaphorin 7a and Alternative Macrophage Activation in Idiopathic Pulmonary Fibrosis - Erica Herzog, M.D. PhD
This research examines the relationship between Semaphorin 7a (Sema 7a) , a neuronal guidance protein with important immune effects on the development of lung fibrosis. Prior studies in our laboratory indicate that this protein is important for the development of lung fibrosis in animal models, and also affects the function of specialized immune cells called alternatively activated . We have recently shown that these specialized macrophages are required for the induction of fibrosis in animals and are found with increased frequency in IPF patients. The studies outlined in this proposal will define, for the first time, the mechanism(s) though which Semaphorin 7a regulates the alternative activation of macrophages and their profibrotic phenotype in animal models and in samples from subjects with IPF. It is hoped that these studies will allow for the development of new therapies for this untreatable disease.
Protection from Inflammation-Induced Pulmonary Fibrosis by IL-22 - Philip Simonian, MD.
Studies in our laboratory are ongoing to better understand how chronic inflammation causes lung fibrosis. We have identified a novel protein, Interleukin 22, that limits both lung inflammation and fibrosis. This novel protein appears to protect lung epithelial cells from damage that results in lung fibrosis. Therefore, Interleukin 22 has the potential to arrest lung inflammation and pulmonary fibrosis and could represent a much needed breakthrough in the fight against pulmonary fibrosis that occurs as a result of many lung diseases. Phase I trials are currently being planned with the goal of enrolling patients in the next year.
Endoplasmic reticulum (ER) stress induces epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AEC) - Beiyun Zhou, PhD
In addition to activation/proliferation of scar-producing cells (fibroblasts) normally resident in the lung, fibroblasts can also arise from cells lining the gas-exchange surface of the lung (epithelial cells) through a process called epithelial-mesenchymal transition (EMT). During EMT, epithelial cells change into fibroblasts in response to environmental stimuli and/or injury. Endoplasmic reticulum (ER) stress, a form of insult arising from such stimuli as virus infection and oxidant injury, has been implicated in death of epithelial cells in IPF and disease causation. We will investigate the hypothesis that ER stress also induces EMT in epithelial cells thereby contributing directly to fibrosis. Understanding the mechanisms whereby ER stress contributes directly to fibroblast accumulation in IPF should provide new insights into the causes of pulmonary fibrosis that may in turn offer novel therapeutic strategies for this otherwise fatal disease
PROJECTS AWARDED PRIOR TO 2010
MicroRNA Regulation in IPF - Melissa Piper, PhD
Despite extensive amounts of research, there are large gaps in understanding the underlying molecular, biochemical, genetic, and cellular mechanisms of pulmonary fibrosis (PF). Many studies have identified numerous genes and proteins differentially expressed in this disease, but the mechanisms governing the control of their expression and their involvement in the development of PF is still unknown. Recently, our laboratory identified small regulatory molecules that are absent in PF that are involved in turning off these genes and proteins. In pre-clinical testing, we found that a FDA approved chemotherapeutic drug induces the expression of these regulatory molecules leading to the decrease expression of pulmonary fibrosis associated genes and reduction in lung fibrosis. Based on these observations, we intend to begin a phase II clinical to examine the efficacy of this treatment for patients with PF. As demonstrated in preliminary studies, we also anticipate that these studies will lead to better treatment options for individuals with IPF.
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) in the progression of pulmonary fibrosis. - Andrew Tager, M.D.
We have recently found that two of the most important chemicals regulating the processes that lead to fibrosis are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). We have found that mice in which the actions of LPA are blocked are dramatically protected in a commonly used mouse model of human pulmonary fibrosis, and that the levels of LPA are elevated in the lungs of patients suffering from IPF. We have found that LPA may be a particularly important chemical in IPF, because it does many things that contribute to fibrosis, including promoting (a) death of the epithelial cells lining the airspaces, (b) abnormal leakiness of the lung's blood vessels, and (c) exuberant accumulation of lung fibroblasts, the cells that actually make scar tissue. These results suggest that blocking the actions of LPA could help prevent the progression of pulmonary fibrosis, and based on our findings, drugs that block LPA are currently under development for fibrosis. In contrast to our results with LPA, we have found that blocking the actions of S1P dramatically worsens pulmonary fibrosis in our mouse model. We have found that in opposition to LPA, S1P resolves the abnormal leakiness of the lung's blood vessels, and prevents inflammatory cells from entering the lung. These results suggest that enhancing the actions of S1P could help prevent the progression of fibrosis, and be another strategy for treating IPF. Our research supported by the Coalition for Pulmonary Fibrosis has therefore led to the identification of two new strategies that may ultimately help to treat the devastating disease of IPF.
Contribution of EMT to Pulmonary Fibrosis - Harikrishna Tanjore, PhD
In Idiopathic pulmonary fibrosis (IPF), fibroblasts are key effector cells responsible for deposition of interstitial collagen and extracellular matrix. Although it is known that fibroblasts are key effectors in lung fibrosis, the origins of these cells are not well defined. Potential sources include resident interstitial fibroblasts, bone marrow derived progenitor cells, and transition of epithelium to the fibroblast phenotype, a process termed as epithelial-mesenchymal transition (EMT). While EMT is important during embryonic development and in metastasis of epithelial malignancies, the extent to which EMT contributes to lung fibrosis is unknown. For this proposal, we developed the following hypothesis: Epithelial to mesenchymal transition (EMT) derived fibroblasts represent a phenotypically distinct population of effector cells in lung fibrosis. EMT is induced by TGF? signaling in alveolar epithelium and plays a pivotal role in determining whether the response to tissue injury leads to normal repair or lung fibrosis.
VEGF: Marker or mediator of lung injury in pulmonary fibrosis? - Sonye Danoff, M.D. PhD
Recent studies using transgenic mice in which VEGF is over-expressed in lung demonstrate that VEGF signaling is sufficient to initiate a cascade of inflammation and fibrosis. We propose to test the hypothesis that locally elevated levels of vascular endothelial growth factor (VEGF) in the lungs of patients with autoimmune pulmonary fibrosis contribute to autoantigen recognition and inflammation. We hypothesize that VEGF exerts its effect on dendritic cells (DCs), the major antigen-presenting cell. Successful completion of these studies will provide novel insights into the mechanism of disease pathogenesis by characterizing the inflammatory milieu associated with pulmonary inflammation and fibrosis in antisynthetase syndrome. It will validate VEGF as a marker of disease activity which could serve as a monitor of therapeutic efficacy. Further, identification of VEGF as a mediator of inflammation. in antisynthetase syndrome would be a first step toward developing a new therapeutic strategy in the treatment of this disorder, as well as other forms of collagen vascular-associated pulmonary fibrosis.
WHAT'S NEXT?
Understanding that the search for answers to PF is in relatively early stages (Cystic Fibrosis, for example, which now has treatments, has been studied for decades compared with the very recent attention paid to PF), we feel there is reason to be optimistic. There is the widening understanding of possible actions behind the fibrotic activity, and the increased research effort not only by individuals and pharmaceuticals, but also via the IPFnet consortium working together to solve the puzzle.
The CPF firmly believes that increased public awareness is absolutely key to generating additional funding and interest in this disease. Pharmaceuticals are already responding to the fact that the patient body increase will ultimately provide them with a substantial market and it is hoped that will drive even more investment on the part of those companies. The government must also increase its investment because the cost of care for the larger patient group will ultimately far outweigh the cost of finding treatments.
