Histochemical and cellular changes accompanying the appearance of lung fibrosis in an experimental mouse model for Hermansky Pudlak syndrome

Hermansky Pudlak syndrome (HPS) is a heterogeneous recessive genetic disease with a tendency to develop lung fibrosis with aging. A mouse strain with two mutant HPS genes affecting separate vesicle trafficking pathways, C57BL/6-Hps1ep-Ap3b1pe, exhibits severe lung abnormalities at young ages, including enlarged alveolar type II (ATII) cells with giant lamellar bodies and foamy alveolar macrophages (AMs), which are readily identified histologically. In this study, the appearance of lung fibrosis in older animals was studied using classical histological and biochemical methods. The HPS double mutant mice, but not Chediak Higashi syndrome (C57BL/6-Lystbg-J-J, CHS) or C57BL/6J black control (WT) mice, were found to develop lung fibrosis at about 17 months of age using Masson trichrome staining, which was confirmed by hydroxyproline analysis. TGF β1 levels were elevated in bronchial alveolar lavage samples at all ages tested in the double mutant, but not WT or CHS mice, indicative of a prefibrotic condition in this experimental strain; and AMs were highly positive for this cytokine using immunohistochemistry staining. Prosurfactant protein C staining for ATII cells showed redistribution and dysmorphism of these cells with aging, but there was no evidence for epithelial-mesenchymal transition of ATII cells by dual staining for prosurfactant C protein and α-smooth muscle actin. This investigation showed that the HPS double mutant mouse strain develops interstitial pneumonia (HPSIP) past 1 year of age, which may be initiated by abnormal ATII cells and exacerbated by AM activation. With prominent prefibrotic abnormalities, this double mutant may serve as a model for interventive therapy in HPS

Comparative Proteomic Analysis of Lung Lamellar Bodies and Lysosome-Related Organelles

Pulmonary surfactant is a complex mixture of lipids and proteins that is essential for postnatal function. Surfactant is synthesized in alveolar type II cells and stored as multi-bilayer membranes in a specialized secretory lysosome-related organelle (LRO), known as the lamellar body (LB), prior to secretion into the alveolar airspaces. Few LB proteins have been identified and the mechanisms regulating formation and trafficking of this organelle are poorly understood. Lamellar bodies were isolated from rat lungs, separated into limiting membrane and core populations, fractionated by SDS-PAGE and proteins identified by nanoLC-tandem mass spectrometry. In total 562 proteins were identified, significantly extending a previous study that identified 44 proteins in rat lung LB. The lung LB proteome reflects the dynamic interaction of this organelle with the biosynthetic, secretory and endocytic pathways of the type II epithelial cell. Comparison with other LRO proteomes indicated that 60% of LB proteins were detected in one or more of 8 other proteomes, confirming classification of the LB as a LRO. Remarkably the LB shared 37.8% of its proteins with the melanosome but only 9.9% with lamellar bodies from the skin. Of the 229 proteins not detected in other LRO proteomes, a subset of 34 proteins was enriched in lung relative to other tissues. Proteins with lipid-related functions comprised a significant proportion of the LB unique subset, consistent with the major function of this organelle in the organization, storage and secretion of surfactant lipid. The lung LB proteome will facilitate identification of molecular pathways involved in LB biogenesis, surfactant homeostasis and disease pathogenesis

PIGMENTATION IN THE ORANGE TUNICATE, ECTEINASCIDIA TURBINATA

Volume: 149Start Page: 178End Page: 18

Insights into the rise in HIV infections, 2001 to 2008: a Bayesian synthesis of prevalence evidence.

OBJECTIVE: To estimate trends in prevalence of HIV infection, undiagnosed and total, among adults aged 15-44 years in England and Wales since 2001. DESIGN: Multiple surveillance systems and survey data are available to inform different aspects of the HIV epidemic in England and Wales. To coherently and consistently combine this information to estimate trends in HIV prevalence, we apply a multiparameter evidence synthesis in a Bayesian statistical framework. METHODS: The study population is stratified by exposure group and region of residence. We synthesize data from behavioural and community surveys, unlinked anonymous seroprevalence surveys, and an annual survey of individuals with diagnosed HIV infection. Prevalence estimates are given with 95% credible intervals. RESULTS: The estimated number of prevalent HIV infections in 15-44-year-olds has increased from 32,400 (29,600-35,900) in 2001 to 54,500 (50,500-59,100) in 2008, corresponding to an estimated prevalence of 1.5 per 1000 (1.4-1.7) rising to 2.4 per 1000 (2.3-2.6) in 2008. A rise in prevalence of diagnosed infection contributes substantially to the increase. There is no evidence of a statistically significant decrease in the prevalence of undiagnosed infection. The proportion of infections that are diagnosed has therefore also increased. CONCLUSION: Although the increase in the proportion of infections that are diagnosed is encouraging, the rise in HIV prevalence and lack of evidence of a decrease in prevalence of undiagnosed infection suggest that diagnosis rates are not high enough to reduce the pool of individuals unaware of their infection and that new infections must be occurring

Hiv treatment as prevention: Models, data, and questions-towards evidence-based decision-making

textabstractAntiretroviral therapy (ART) for those infected with HIV can prevent onward transmission of infection, but biological efficacy alone is not enough to guide policy decisions about the role of ART in reducing HIV incidence. Epidemiology, economics, demography, statistics, biology, and mathematical modelling will be central in framing key decisions in the optimal use of ART. PLoS Medicine, with the HIV Modelling Consortium, has commissioned a set of articles that examine different aspects of HIV treatment as prevention with a forward-looking research agenda. Interlocking themes across these articles are discussed in this introduction. We hope that this article, and others in the collection, will provide a foundation upon which greater collaborations between disciplines will be formed, and will afford deeper insights into the key factors involved, to help strengthen the support for evidence-based decision-making in HIV prevention