Exposure to airborne particulate matter (PM) is accepted as a major risk factor for respiratory disorders. Its link to the early origin of allergic disease and asthma in children - a susceptible population - is increasingly recognized. An aberrant host response to PM exposure in early life could be a one of the major determinants that control enhanced susceptibility. There is recent, compelling evidence that the pulmonary surfactant is an important target for PM, and that the most abundant lung collectins, epithelial-derived surfactant protein (SP)-A, is critically involved in pulmonary host response, so that alterations of its production or biological function may lead to aberrant immune response and set the stage for the development of disease. The molecular mechanisms that regulate SP-A expression and production and how their alteration may confer increased susceptibility to PM in infants and young children are not known. We have recently developed in vitro and in vivo systems to define the cellular and molecular interactions between PM and SP-A, and have found profound age-dependent changes in the functional and immune behavior of the lung that lead to a deficiency of SP-A. These findings provide support for our hypothesis that the pulmonary type II cell is a primary target for PM and a key regulator of the host response that is dependent upon changes in surfactant protein-A gene expression and homeostasis. In this application, we will use a rigorous and multidisciplinary approach to define the cellular regulation of SP-A and its role in the enhanced susceptibility to PM that we have observed in our experiments.
Two specific aims are proposed to test our hypothesis.
In Aim 1, we will define the effect of PM on the cellular regulation of SP-A using isolated human type II cells in primary culture.
In Aim 2, we will characterize the mechanisms by which PM exposure disrupts SP-A homeostasis in mice as a function of age. These studies will provide new mechanistic information on children's enhanced vulnerability to airborne pollutants, improve our knowledge of the role played by lung collectins in host defense system, and provide insights on age-dependent functional and cellular events that could be used in prevention and therapeutic measures ? ?
| Bruce, Shirley R; Atkins, Constance L; Colasurdo, Giuseppe N et al. (2009) Respiratory syncytial virus infection alters surfactant protein A expression in human pulmonary epithelial cells by reducing translation efficiency. Am J Physiol Lung Cell Mol Physiol 297:L559-67 |
| Alcorn, Joseph L; Stark, James M; Chiappetta, Constance L et al. (2005) Effects of RSV infection on pulmonary surfactant protein SP-A in cultured human type II cells: contrasting consequences on SP-A mRNA and protein. Am J Physiol Lung Cell Mol Physiol 289:L1113-22 |
