Idiopathic pulmonary fibrosis (IPF) remains a disease with a dire prognosis with patients progressing to respiratory failure and death within a few years of diagnosis. Over the past decade, increasing evidence implicates alveolar epithelial cell (AEC) dysfunction, fibroblast activation, and interactions between these two critical cell populations as pivotal in the pathogenesis of IPF. Unfortunately, many of the factors involved in disease pathogenesis remain unknown, and IPF remains a disease with a dire prognosis and no effective treatments. Over the past several years, it has been increasingly recognized that pathways involved in lung and other organ development that are subsequently quiescent in unstressed adult tissues may have important functions in response to injury and subsequent tissue remodeling. The sonic hedgehog pathway (SHH) is critical to lung development, with SHH expressed by the distal epithelium serving as a ligand for receptors on the surrounding mesenchymal cells, with the SHH dependent interactions between the epithelial and mesenchymal cell populations leading to the normal branching of the lung. Following lung development SHH is not expressed in the normal adult lung, but recent evidence suggests that it is again expressed in the alveolar epithelium in IPF, raising questions on this pathway's role in the fibrotic process. Our preliminar data reveal that SHH expression is upregulated in the lung with bleomycin induced lung injury and fibrosis. Furthermore, inhibition of the SHH pathway with the chemical agent cyclopamine attenuates bleomycin induced lung fibrosis. However, regulation of the SHH pathway likely has cell specific effects as attenuation of SHH signaling in the AEC population augments bleomycin induced fibrosis while attenuation in the lung fibroblast population decreases lung fibrosis. The proposed studies in this application will define critical roles the SHH pathway plays in the way these two cell populations orchestrate lung repair following injury, leading to important new insights into the aberrancies of lung remodeling that are found in IPF pathogenesis. The hypothesis of this proposal is as follows: SHH is produced by AECs following injury and serves to activate lung fibroblasts and induce myofibroblast differentiation. In addition, SHH signaling i the alveolar epithelium is required for normal alveolar repair. Competing effects of the SHH pathway on AECs and fibroblasts influences whether the response to injury results in normal lung repair or fibrosis. To test this hypothesis, the following specific aims will be evaluated: 1 To determine whether global inhibition of the SHH pathway attenuates lung fibrosis following bleomycin treatment;2) To investigate the impact of SHH signaling on lung fibroblast phenotype and function;3) To define the requirement for the alveolar epithelium in production of and response to hedgehog ligands following injury;and 4) To identify whether SHH is required for re-epithelialization in a model of progressive lung fibrosis. In these investigations, we will test the utility of inhibiting the SHH pathway with cyclopamine in attenuating bleomycin induced lung fibrosis and then dissect out AEC and fibroblast specific aspects of SHH pathway regulation using transgenic mouse approaches that delete SHH pathway components specifically in these two cell populations. Through these experiments, we will determine how modulation of the SHH pathway in both the AEC and fibroblast populations impacts response to initial lung injury, deposition of collagen and extracellular matrix with fibrosis, and resolutionof fibrosis in the bleomycin model. Defining key aspects by which the SHH pathway regulates lung remodeling and repair in these two cell populations could lead to new insights into IPF pathogenesis and identification of future therapeutic targets for this still deadly disease.
Pulmonary fibrosis, characterized by scarring of the lung tissue leading to progressive shortness of breath is frequently encountered in the United States Veteran population. Among the different types of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF) stands quite prominent as one of the most common and also most deadly with most individuals dying from the disease within a few years of diagnosis. Unfortunately, the cause remains unknown, no curative treatment is available, and prognosis remains extremely poor. To have the best chance of eventually developing a good therapy for IPF, much further knowledge regarding critical pathways in disease pathogenesis is required. This research proposal aims to define the role that the sonic hedgehog pathway plays in this disease, providing new clues to factors involved in disease initiation and progression. This valuable information will eventually be used to develop treatments for this devastating disease that continues to cause respiratory failure and death in many United States Veterans.
|Kropski, Jonathan A; Pritchett, Jason M; Zoz, Donald F et al. (2015) Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease. Am J Respir Crit Care Med 191:417-26|
|Shaver, Ciara M; Grove, Brandon S; Putz, Nathan D et al. (2015) Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor. Am J Respir Cell Mol Biol 53:719-27|
|Cogan, Joy D; Kropski, Jonathan A; Zhao, Min et al. (2015) Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med 191:646-55|
|Kropski, Jonathan A; Mitchell, Daphne B; Markin, Cheryl et al. (2014) A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia. Chest 146:e1-e7|