Abstract
BackgroundPulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pulmonary vascular disease (PVD). 99mTc-PulmoBind is a novel imaging agent that binds to the adrenomedullin (AM) receptor on the pulmonary microvascular endothelium. SPECT imaging employing the endothelial cell tracer 99mTc-PulmoBind was used to assess PVD associated with lung fibrosis.MethodsRats with selective right lung bleomycin-induced fibrosis were compared to control rats. SPECT imaging was performed after three weeks with 99mTc-PulmoBind and 99mTc-macroaggregates of albumin (MAA). PH and right ventricular (RV) function were assessed by echocardiography. Lung perfusion was evaluated by fluorescent microangiography. Lung AM receptor expression was measured by qPCR and by immunohistology. Relevance to human IPF was explored by measuring AM receptor expression in lung biopsies from IPF patients and healthy controls.ResultsThe bleomycin group developed preferential right lung fibrosis with remodeling and reduced perfusion as assessed with fluorescent microangiography. These rats developed PH with RV hypertrophy and dysfunction. 99mTc-PulmoBind uptake was selectively reduced by 50% in the right lung and associated with reduced AM receptor expression, PH and RV hypertrophy. AM receptor was co-expressed with the endothelial cell protein CD31 in alveolar capillaries, and markedly reduced after bleomycin. Quantitative dynamic analysis of 99mTc-PulmoBind uptake in comparison to 99mTc-MAA revealed that the latter distributed only according to flow, with about 60% increased left lung uptake while left lung uptake of 99mTc-PulmoBind was not affected. Lung from human IPF patients showed important reduction in AM receptor expression closely associated with CD31.ConclusionsSPECT imaging with 99mTc-PulmoBind detects PVD and its severity in bleomycin-induced lung fibrosis. Reduced AM receptor expression in human IPF supports further clinical development of this imaging approach.
Highlights
Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome
Model of selective right lung injury and fibrosis induced by bleomycin In order to test the capacity of PulmoBind to detect localized pul‐ monary vascular disease (PVD) in lung fibrosis we used a model of selective right lung fibrosis
There was no difference in left ventricle weight and severe right ventricular (RV) hypertrophy measured from the Fulton index (Fig. 1)
Summary
Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pul‐ monary vascular disease (PVD). SPECT imaging employing the endothelial cell tracer 99mTcPulmoBind was used to assess PVD associated with lung fibrosis. Chronic lung diseases, including idiopathic pulmonary fibrosis (IPF), can be associated with pulmonary vascular disease (PVD) [1] leading to pulmonary hypertension (PH). A recent review concluded that in view of the high prevalence of chronic lung diseases and the much worse prognosis conferred by associated PH: “further investigations are required in order to improve early diagnosis and provide better clinical management” [4]. There is no imaging modality that can provide early specific diagnosis of PVD
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