Faculty Bibliography

Asbestosis is a fibrotic and inflammatory interstitial lung disease occurring after chronic occupational exposure to asbestos. An alveolitis has been described with activated alveolar macrophages and increased neutrophils as sampled by bronchoalveolar lavage (BAL). Animal models and in vitro studies demonstrate that asbestos can stimulate alveolar macrophages to release neutrophil chemotactic factor. We performed BAL on 18 nonsmoking individuals with asbestos exposure and observed a twofold increase in percent neutrophils recovered. Alveolar macrophages cultured in vitro from the asbestos-exposed individuals spontaneously released significant amounts of the neutrophil chemotaxin, interleukin-8 (IL-8). In addition, the alveolar macrophages expressed a 2.7-fold increase in steady state mRNA levels compared to unexposed normal controls utilizing the reverse transcriptase/polymerase chain reaction. In vitro experiments confirmed that crocidolite or chrysotile asbestos could stimulate the release of IL-8 from mononuclear phagocytes in a dose-dependent fashion. We conclude that asbestos exposure causes a mild neutrophilic alveolitis, and that IL-8 is one potential mediator capable of contributing to this inflammation in the lower respiratory tract

Idiopathic pulmonary fibrosis (IPF) is characterized by activated alveolar macrophages (AM), alveolar epithelial cell proliferation and interstitial matrix, and immune complex deposition. Spontaneous release of competence and progression-type growth factors and their associated binding proteins may contribute to the pathologic features of IPF. To study the role of insulin-like growth factor (IGF) molecules in IPF we evaluated spontaneous release of IGF-I and IGFBP-3 in bronchoalveolar lavage cells from control subjects and from patients with IPF. IGF-I levels were similar compared with those in control subjects. In contrast, IGFBP-3 was significantly increased in IPF. In situ hybridization of open lung biopsies showed IGF-I to be abundant in IPF lung tissue in alveolar macrophages, interstitial mesenchymal cells, and epithelial cells. Northern, Western ligand blotting, reverse transcription PCR, and radioimmunoassay suggested that immune complexes stimulate expression of IGFBP-3 in mononuclear phagocytes in a time- and dose-dependent manner bearing strong similarities to stimulation by LPS. These data are compatible with the hypothesis that IGFBP-3 increases the bioactivity of IGF-I derived from a variety of lung tissues contributing to the fibrosis and remodeling seen in IPF

Insulin-like growth factor (IGF) I has important growth regulatory functions in normal growth and development. IGF-I is also a mitogen for a number of cancer cell lines; however, its autocrine effect has not been well established. In this study, the expression of IGF-I, its receptor, and its major serum-binding protein were examined in 5 normal human mesothelial (NHM) cell samples and 11 pleural mesothelioma cell lines. All NHM cells and mesothelioma cell lines expressed IGF-I, IGF-binding protein 3 (IGFBP-3), and IGF-I receptor mRNA by either Northern blot or reverse transcription polymerase chain reaction analysis. IGF-I (0.136 +/- 0.024 ng/ml, mean +/- SEM) and IGFBP-3 (18.5 +/- 3.2 ng/ml) proteins were readily detected in the conditioned medium of mesothelioma cell lines but were not greater than corresponding measurements in that of NHM cells (IGF-I, 0.120 +/- 0.080 ng/ml; IGFBP-3, 15.9 +/- 1.3 ng/ml). Exogenous recombinant IGF-I stimulated cell proliferation of NHM cells, demonstrating the presence of a functional IGF-I receptor. Our results suggest that IGF-I may function as an autocrine growth stimulus in normal proliferating mesothelial cells, which may contribute to their malignant transformation