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<p>Due to its nature and function, the lungs are confronted with the unique challenge of rapidly eliminating inhaled pathogens and particulates while limiting inflammatory responses. A disruption in this immune homeostasis may result in respiratory inflammatory diseases, such as allergies or asthma. The alveolar epithelial type II cell and its secretory product, surfactant protein A (SP-A), have been linked to roles in adaptive immunity in the lung. The discovery that type II cells constitutively express major histocompatibility complex class II (MHC II) suggested that type II cells may function to present antigen to T cells. Studies in vitro demonstrated that SP-A inhibits the maturation of bone marrow-derived dendritic cells. The goal of this work was to determine how type II cells and SP-A may be functioning to regulate adaptive immunity in the lungs. The hypothesis tested is that type II cells and SP-A suppress the activity of T cells and dendritic cells in the lungs. As T cells and dendritic cells are critical for the initiation and function of the adaptive immune response, the inhibition of T cell and dendritic cell activity would limit inflammation in the lungs. Although isolated murine type II cells expressed MHC II, they did not express detectable levels of the costimulatory molecules CD80 and CD86 and were poor activators of T cells. Upregulation of MHC II on type II cells by interferon-gamma stimulation did not enhance the ability of type II cells to activate T cells. Instead, the type II cells suppressed T cells from subsequent activation to antigen in an antigen-dependent manner, indicative of tolerance. T cells pre-incubated with type II cells and antigen were suppressed from further activation, even after removal of the type II cells. Using a model of pulmonary infection with Mycoplasma pneumoniae, wildtype mice were found to have fewer mature dendritic cells in the mediastinal lymph nodes than SP-A null mice. The presence of SP-A in the wild-type mice had a suppressive effect on the M. pneumoniae-induced maturation of dendritic cells in the lungs. Together, the data demonstrate that type II cells and SP-A participate in the adaptive immune response by suppressing the activity of T cells and dendritic cells in the lungs.</p> / Dissertation

<p>Organophosphates (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism. This dissertation examines the cellular mechanisms underlying metabolic dysfunction after early-life OP exposure. We administered diazinon (DZN) or parathion (PRT) to rats on postnatal days (PN) 1-4 at doses straddling the threshold for cholinesterase inhibition and assessed the longitudinal effects on hepatic and cardiac cell function mediated through the adenylyl cyclase (AC) signaling cascade, which controls neuronal and hormonal inputs that regulate hepatic glucose metabolism and cardiac contractility. Specifically, we investigated if outcomes of metabolic dysfunction are related to hepatic AC dysregulation. In the liver, DZN elicited parallel upregulation of AC activity itself and of the responses to AC stimulants acting at beta-adrenergic receptors (BARs), glucagon receptors, or G-proteins. The effects intensified from adolescence to adulthood. In contrast, PRT elicited upregulation in adolescence that waned by adulthood. Effects on the liver were more substantial than those in the heart and a brain region (cerebellum) that shares similar AC cascade responses. These findings indicate that OPs produce lasting hepatic AC gain-of-function and alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction. Since the effects are unrelated to cholinesterase inhibition, the various OPs differ in their net impact on AC signaling.</p> <p>We then examined whether OPs directly affect the expression or function of AC signaling elements, using PC12 cells to evaluate effects on transcription of AC pathway genes and on protein function. Whereas different OPs had disparate effects on gene transcription, they had nearly identical effects at the protein level, suggesting that programming occurs post-transcriptionally. We further found that otherwise unrelated developmental toxicants (OPs, dieldrin, nickel) can nevertheless converge on similar outcomes for their impact on the AC pathway, providing a common pathway by which diverse agents can lead to metabolic dysfunction.</p> <p>The standard view of OPs as developmental toxicants that exclusively target the nervous system requires substantial revision. Through their effects on hepatic cell signaling and other metabolic processes, early-life chemical exposures may play an important role in the worldwide increase in obesity and diabetes.</p> / Dissertation

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3264. Adviser: Renee A. Reijo Pera.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3265. Adviser: Ronald D. Vale.

Thesis (Ph.D.)--Indiana University, Dept. of Biology, 2009. / Title from PDF t.p. (viewed on Feb. 8, 2010). Source: Dissertation Abstracts International, Volume: 70-05, Section: B, page: 2653. Adviser: James D. Bever.