Idiopathic pulmonary fibrosis (IPF) is a severe, chronic, aging-associated respiratory illness of unknown cause in which normal lung tissue is progressively replaced by scarring (fibrosis). This steady accumulation of scarring leads to impaired lung function, difficulty breathing, and eventually death, with an average survival of only 3-5 years after diagnosis. The current prevailing hypothesis is that IPF occurs as a result of aberrant or over-exuberant wound-healing responses to repetitive, microscopic lung injuries, due to a complex interplay of aging, host susceptibility, and environmental factors. One hallmark of lung injury is extravascular coagulation with subsequent intra-alveolar fibrin deposition. The overall hypotheses of this project are that in IPF 1) there is ongoing lung injury, 2) aging is associated with more severe lung injury, and 3) the extent of lung injury correlates with disease activity and pace of progression. To assess ongoing lung injury in IPF patients, we will use a novel molecular imaging technique, fibrin-PET, to measure lung fibrin deposition in human subjects. Specifically, we propose the following:
Specific Aim 1 : To determine whether ongoing lung injury can be detected in the lungs of IPF patients by fibrin-PET imaging. We hypothesize that IPF patients have ongoing lung injury, and that increased lung fibrin deposition is a manifestation of this injury. To test this hypothesis, we will perform positron emission tomography (PET) with a fibrin-specific probe, 64Cu-FBP8, to compare lung fibrin deposition in IPF patients and healthy controls.
Specific Aim 2 : To determine whether aging is associated with increased lung injury in IPF. We hypothesize that aging is associated with a greater extent of lung injury in IPF. To test this hypothesis, we will determine whether the extent of lung fibrin deposition, as determined by fibrin-PET imaging, correlates with increasing age in IPF.
Specific Aim 3 : To determine whether the extent of lung injury correlates with disease activity in IPF. We hypothesize that the extent of ongoing lung injury correlates with pace of progression, i.e. disease activity, in IPF. To test this hypothesis, we will determine whether the extent of lung fibrin deposition, as determined by fibrin-PET imaging, correlates with rate of forced vital capacity (FVC) decline in IPF.
Idiopathic pulmonary fibrosis (IPF) appears to be increasing in incidence worldwide, and this trend will likely continue as the population ages. It is a disease in dire need of scientific breakthroughs, as available medical therapies can slow the loss of lung function in IPF, but they do not cure the disease or completely stop its progression. If successful, these proposed studies would firmly establish the biological relevance of ongoing lung injury in IPF and set the stage for future studies assessing fibrin-PET as a tool for 1) predicting IPF progression and 2) predicting which IPF patients may be more likely to respond to therapeutic interventions targeting lung injury and the coagulation cascade.
