Although alveolar epithelial type II cells (AECII) form the barrier of alveolar spaces and produce surfactants to maintain lung integrity, the unique AECII population in the lung may also play a critical role in anti-microbial immunity by secreting cytokines, such as monocyte chemoattractant protein (MCP-1) against P. aeruginosa (PA) infection. However, the mechanism of cytokine secretion is largely unknown. Our long-term goal is to understand mechanisms of lung host defense, thereby identifying new strategies for treating bacterial infection. Our objective of this application is to characterize the mechanism of cytokine secretion by AECII. We hypothesize that AECII play immune roles by secreting cytokines, which is regulated through a mechanism of membrane microdomain reorganization. We have formulated this hypothesis based on our recent studies and two separate lines of evidence. First, in a high purity cell population, we found that a conditioned medium from PA-infected primary AECII enhanced AM immunity. On the other hand, the importance of lipid rafts (membrane microdomains) for innate immunity has been indicated by the fact that CF patients, who are particularly at risk for PA infection, may often suffer from abnormal lipid raft function due to ceramide deficiency and fatty-acid imbalance. Consistent with this, we showed that lipid rafts may be involved in the secretion of the cytokine MCP-1, which is localized in ceramide-rich rafts. Our rationale is that elucidating the relevant mechanism in ceramide-rich microdomains will define a general mechanism for cytokine secretion. Our laboratory is ideally suited for this research since we have the requisite expertise in AECII isolation, PA infection, and advanced biochemical techniques. To test our hypothesis, we propose the following two specific aims:
Specific Aim 1 : To characterize dynamic reorganization of membrane microdomains in regulating cytokine secretion in AECII and in mice using imaging tools. Our working hypothesis is that PA infection initiates dynamic changes in membrane microdomains that impact cytokine production.
Specific Aim 2 : To define the mechanism by which membrane microdomains regulate key cytokines required for PA defense. Our hypothesis is that ceramide is generated by hydrolysis and translocated to specialized domains, where it initiates signaling for production of MCP-1. Due to the important role of cytokines in various physiological and pathological conditions, these novel mechanisms will improve understanding of cytokine secretion for other types of cells, pathogens, and inflammatory situations, and thereby identifying new therapeutic targets.
Although alveolar epithelial type II cells (AECII) are structural and progenitor cells in the lung, they also provide immune defense by secreting cytokines. This unique immunity may critically increase host defense against P. aeruginosa (PA), a bacterium that causes severe infections in immunodeficient individuals, such as AIDS, tuberculosis and cystic fibrosis. We hypothesize that AECII secrete cytokines through changes in cell membrane microdomains, a novel mechanism that may impact many disease processes. Thus, our research will provide new insights into the development of novel treatment for this recurrent infection.
|Sun, Yuyang; Sukumaran, Pramod; Varma, Archana et al. (2014) Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells. Biochim Biophys Acta 1843:1839-50|
|Wang, W; Ye, Y; Li, J et al. (2014) Lyn regulates cytotoxicity in respiratory epithelial cells challenged by cigarette smoke extracts. Curr Mol Med 14:663-72|
|Zhao, Kelei; Li, Yi; Yue, Bisong et al. (2014) Genes as early responders regulate quorum-sensing and control bacterial cooperation in Pseudomonas aeruginosa. PLoS One 9:e101887|
|Zhao, Yang; Ye, Yan; Zhou, Xikun et al. (2014) Photosensitive fluorescent dye contributes to phototoxicity and inflammatory responses of dye-doped silica NPs in cells and mice. Theranostics 4:445-59|
|Ye, Yan; Li, Xuefeng; Wang, Wenxue et al. (2014) Atg7 deficiency impairs host defense against Klebsiella pneumoniae by impacting bacterial clearance, survival and inflammatory responses in mice. Am J Physiol Lung Cell Mol Physiol 307:L355-63|
|Zhao, Kelei; Li, Wujiao; Kang, Chunlan et al. (2014) Phylogenomics and evolutionary dynamics of the family Actinomycetaceae. Genome Biol Evol 6:2625-33|
|Li, Yi; Gan, Chang-pei; Zhang, Shuang et al. (2014) FIP200 is involved in murine pseudomonas infection by regulating HMGB1 intracellular translocation. Cell Physiol Biochem 33:1733-44|
|Chen, Jiao; Li, Xuefeng; Wu, Xu et al. (2014) Au-Silica nanowire nanohybrid as a hyperthermia agent for photothermal therapy in the near-infrared region. Langmuir 30:9514-23|
|Cao, Qiao; Wang, Yue; Chen, Feifei et al. (2014) A novel signal transduction pathway that modulates rhl quorum sensing and bacterial virulence in Pseudomonas aeruginosa. PLoS Pathog 10:e1004340|
|Wu, Xu; Wu, Min; Zhao, Julia Xiaojun (2014) Recent development of silica nanoparticles as delivery vectors for cancer imaging and therapy. Nanomedicine 10:297-312|
Showing the most recent 10 out of 17 publications