Idiopathic pulmonary fibrosis (IPF) is a disease that culminates in progressive loss of pulmonary function and deposition of extracellular matrix (ECM). Additionally, many IPF patients will experience an acute worsening of symptoms due to known causes (e.g. infection) or of idiopathic nature termed """"""""acute exacerbations"""""""". Circulating, bone-marrow-derived cells known as fibrocytes (identified by shared leukocyte and mesenchymal markers) may be regulators of IPF pathogenesis. Fibrocyte numbers are increased in patients with IPF and murine fibrosis studies have demonstrated that fibrocytes are 1) recruited to the lung by chemokines 2) adoptive transfer of fibrocytes worsen disease and 3) fibrocyte recruitment correlates with infectious exacerbations. Thus, absolute numbers of fibrocytes, or particular fibrocyte phenotypes, may serve as novel biomarkers in IPF. The IPF network (IPFnet) is the parent organization that will oversee the PANTHER trial which is a multi-center, randomized, double-blind placebo controlled trial to investigate the efficacy of prednisone + azathioprine + N-acetylcysteine (NAC) or NAC alone versus placebo in IPF patients with mild- moderate disease (130 patients in each arm followed up to 67 weeks). The second trial is the STEP trial to test sildenafil in IPF patients with severe disease over a 12 week period (85 patients in both the treatment and placebo arms). All these patients will be well characterized for diagnosis, physiology, disease progression and adverse events. The studies proposed in this grant would take advantage of the large and diverse IPF patient populations enrolled in these trials and the abundant clinical/physiological data collected over time on each patient to perform longitudinal and cross-sectional studies to characterize fibrocyte numbers and phenotypes in an effort to provide mechanistic correlations into the natural history of IPF and response to therapy. In addition, we will compare IPF fibrocyte phenotypes to those obtained from disease-specific control patients including patients with chronic obstructive pulmonary disease (COPD) and scleroderma as well as normal volunteers. We hypothesize that absolute numbers of fibrocytes, or distinctive fibrocyte phenotypes (chemokine receptor expression, collagen synthetic capacity, secretion of pro-fibrotic mediators or proliferation) will correlate with severity of disease at entry, rate of progression of disease, response to therapy and occurrence of acute exacerbations. The IPFnet steering committee recognizes the value of these mechanistic studies and fully supports this application.
Aim 1) To determine whether absolute numbers of fibrocytes or alterations in fibrocyte phenotype differentiate between normal, COPD, scleroderma and IPF subjects.
Aim 2) To determine whether changes in fibrocyte numbers or alterations in fibrocyte phenotype(s) predict severity of disease, changes in physiology or response to therapy in IPF and control patients.
Aim 3) To determine whether changes in absolute numbers of alterations in fibrocyte phenotype(s) correlate with acute deteriorations or differentiate between acute exacerbations of known and unknown cause. Statement of Relevance Fibrocyte phenotypes have been validated as biomarkers in murine models of fibrosis. Our proposed studies would be the first to provide longitudinal and cross sectional analyses of fibrocyte phenotypes as biomarkers in human fibrotic lung disease.
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