This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Idiopathic pulmonary fibrosis (the clinical condition associated with the pathologic diagnosis of usual interstitial pneumonitis) is a progressive fatal disease of unknown etiology. Currently, definitive diagnosis can only be made by surgical lung biopsy, although clinical diagnoses are made in certain patients with characteristic radiographic findings and a suitable clinical history. Accurate diagnosis is essential because related disorders, such as non-specific interstitial pneumonitis are responsive to immunosuppressive therapy and carry a significantly better survival than does idiopathic pulmonary fibrosis. Radiographic techniques currently available are inadequate to differentiate clinically responsive from non-responsive disease, and so many patients must undergo surgical biopsy with the concomitant risks related to these procedures. The goal of the present study is to establish a radiographic technique to quantify radiographic changes in lung parenchyma and vasculature associated with interstitial lung disease which will allow a more precise clinical diagnosis. We will compare two models of fibrosis in mice using tracheal aspiration of bleomycin or silica. Animals will be examined using micro CT at end-inspiration and end-expiration to assess shifts in histogram density which will be related to pathologic findings and degree of fibrosis. Individual animals will be assessed at multiple time points to determine the radiographic pattern of fibrosis over time, and to detect differences between the two models. In addition, pulmonary vasculature will be examined using digital subtraction techniques to assess the changes produced by the fibrotic process, while cardiac output will be estimated using stroke volume measurements. Finally, vasoactive agents will be employed to assess the degree of reversibility in anticipated pulmonary hypertension associated with fibrosis. Multiple mouse strains may be examined including: C57BL/6, C3H/HeJ, 129S1/SvImJ, A/J, BTBR T+ tf/J, FVB/NJ, NOD/LtJ, DBA/2J, BALB/cByJ, B6;129-Igf2, C57BL/6-Tg(ACTB-EGFP)1Osb/J, and C57BL/6x129 ColR/R. Vasoactive agents which may be used to assess vascular changes associated with the fibrotic process include;nitroprusside, nitric oxide, epoprostinol, diltiazem, phenylephrine, and hypoxia.
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