When considered as a group, patients with idiopathic pulmonary fibrosis (IPF) have a poor prognosis and a short median survival. When IPF patients are considered individually however, there is substantial heterogeneity in their clinical course, with some patients having minimally active disease that remains clinically stable for long periods of time while others have very active disease that quickly progresses to respiratory failure. There is increasing recognition that the clinical entity of IPF represents at least several differet clinical phenotypes. Currently however, there are unfortunately no means by which IPF disease activity can be assessed at the time of diagnosis or the clinical course of an individual IPF patient can be confidently predicted. Developing the ability to differentiate IPF patients into different clinical phenotypes at the time of diagnosis would have a dramatic impact on patient care. This knowledge would enable providers to better prognosticate a patient's disease course and may result in preferential early evaluation for lung transplantation for those with rapidly progressive disease. In addition, developing the ability to assess how active a patient's fibrosis is would also greatly facilitate the performance of IPF clinical trials by enabling investigators t enroll subjects more likely to progress during studies. Being able to assess IPF activity would also enable earlier assessments of responses to new therapies. The overarching goal of this proposal is to develop the ability to better assess disease activity in IPF patients with lung molecular imaging and novel plasma biomarkers in order to more accurately predict a patient's clinical course. Fibrosis in IPF is thought to result from aberrant wound healing responses to ongoing lung injury, and consequently disease activity in IPF should reflect the magnitude of that ongoing injury.
In Aim 1, we will develop the ability to visualize lung vascular leak by molecular imaging as a measure of lung injury. Vascular leak is a cardinal response to lung injury that when dysregulated contributes to pulmonary fibrosis, as our group has previously shown. Alveolar-capillary permeability is increased in the lungs of IPF patients, and the extent of that increase has been shown to correlate with disease progression and mortality.
In Aim 2, we will investigate the ability of two novel plasma biomarkers of lung injury, soluble suppression of tumorigenicity-2 (sST2) and soluble Ephrin-B2 (sEphrin-B2), to assess disease activity in IPF. We have found sST2 to be elevated in the plasma of ARDS patients, and others have reported elevations of this biomarker in IPF patients experiencing an acute exacerbation. We have preliminary data that sEphrin-B2 is also released in response to lung injury and is elevated in the plasma of IPF patients. In each aim, we will determine the extent to which our novel measures of lung injury are elevated in IPF patients with progressive disease compared with those who remain stable. If successful, these studies will identify new ways to measure disease activity in IPF and improve the ability to predict the clinical course of individuals with this disease.
Idiopathic pulmonary fibrosis (IPF) is a disease with an overall poor prognosis and short median survival but also has marked individual disease heterogeneity. Some patients progress rapidly, but others may have a disease course marked by prolonged periods of relative stability. The ability to distinguish which patients are more likely to progres rapidly represents an urgent and unmet need for both IPF patient care and research, which the studies proposed in this application seek to address.
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