Hexavalent chromium (Cr(VI)) is in the top 20 compounds of the ATSDR/EPA priority list since it promotes interstitial lung fibrosis, induces asthma, and is recognized as a probable human lung carcinogen. Despite the epidemiological evidence for both occupationally and environmentally-derived pulmonary disease following inhalation of Cr(VI), there are few studies that define the cellular and molecular basis for pathologic changes in the Cr(VI)-exposed lung. Overall Objective: The overall objective of the proposed studies is to define the molecular signaling mechanisms through which non-cytotoxic concentrations of Cr(VI) alter inducible cytokine and profibrotic gene expression in airway and alveolar epithelial cells. We have recently defined a novel pathway through which Cr(VI) inhibits the transcriptional competence of the transcription factor NF-kappaB by promoting recruitment of the essential co-activator CREB-binding protein (CBP) to c-Jun. We hypothesize that Cr(VI)-induced alteration of co-activator recruitment changes the profile of inducible gene expression and potentiates Fas-induced apoptosis. These effects of Cr(VI) favor development of pulmonary fibrosis. Specific Objectives:
Aim 1 of the grant will use human lung cells in culture to define cellular signaling pathways that regulate Cr(VI)-induced recruitment of CBP to specific transcription factors (e.g. c-Jun).
Aim 2 will use these models to demonstrate that competition for CBP is the rate limiting step in Cr(VI)- induced loss of NF-kappaB transactivation. The consequence of a switch in CBP-dependent transcription factor competence on FAS- induced apoptosis and gene expression will be examined.
The final Aim will use normal and unique transgenic mouse models to examine Cr(VI)-induced regulation of transcription factor activity and of inducible pro-apoptotic and pro-fibrotic phenotypic changes in vivo. Significance: The studies will define fundamental epigenetic mechanisms for altered inducible gene expression and increased susceptibility of airway and alveolar epithelial cells to apoptosis following exposure to Cr(VI). Apoptosis of the airway is now recognized as an underlying non-inflammatory mechanism for lung fibrosis. Thus, these studies will translate observations in cell culture into in vivo models of exposure to greatly improve the basic understanding of how Cr(VI) promotes pulmonary diseases.
