Gilbert Morris, PhD, School of Medicine
The Morris laboratory is interested in the molecular biology of lung injury and repair with a particular interest in fibrogenesis and carcinogenesis.
a. Modeling lung tumorigenesis in mice. Our laboratory has demonstrated expression of the p53 tumor suppressor protein at sites of fibrogenesis after inhalation exposure of rodents to asbestos. To characterize p53 function in this rodent model of asbestos-induced lung disease, we prepared transgenic mice that express a dominant negative mutant form of p53 from the surfactant protein C promoter (SPC-DNp53 mice). These animals with inhibited p53 function in the lung epithelium display enhanced fibrogenesis after exposure to bleomycin. A strong correlation exists between mutations in the p53 gene and malignant conversion. The phenotypic alterations of the SPC-DNp53 mice described above have disrupted p53 function in the epithelial cells of the small airways and the peripheral lung. This animal model is being used to study lung carcinogenesis induced by inhaled agents linked to human lung cancer, i.e. cigarette smoke and asbestos, to model the human disease in mice. Moreover, interbreeding SPC-DNp53 mice with mice harboring a mutant K-Ras allele (K-RasLA1) accelerates lung tumor progression.
b. Lung tumor promotion by IL-17. The overwhelming majority of human lung cancers are associated with exposure to cigarette smoke. Recent findings demonstrate that inhaled cigarette smoke elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17 (IL-17), the hallmark cytokine of the Th17 inflammatory phenotype, displays pro- and anti-tumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor progression, we used an autochthonous tumor model (K-rasLA1 mice). IL-17 induced matrix metalloproteinase-9 (MMP-9) protein and mRNA expression in K-rasLA1 mice. In accord with this finding, IL-17 promoted increased MMP-9 expression in mutant K-Ras-expressing murine lung epithelial (mK-Ras-LE) cells in culture, which corresponded to increased cell motility and invasiveness. Our results indicate that IL-17 stimulates lung tumor progression, in part, via enhanced expression of MMP-9 that includes stabilization of the MMP-9 mRNA via altered function of a mRNA splicing factor.
c. Inflammasome repression by cigarette smoke. Inhaled asbestos activates the NLRP3 inflammasome in mice. Our data shows that cigarette smoke represses inflammasome activation. This finding suggests that tobacco smoke most likely impairs fiber clearance, in accordance with previous findings by others. We are exploring the relationship between the immunosuppressive effects of cigarette smoke and the development of lung disease in our murine models. Using inhaled asbestos as an inducer of lung disease allows us to examine mechanisms of fibrogenesis and carcinogenesis in an animal model that develops diseases identical to humans exposed to these 2 toxic substances.
gmorris2@tulane.edu
