The Mammalian Phenotype Ontology as a tool for annotating, analyzing and comparing phenotypic information

The Mammalian Phenotype (MP) Ontology enables robust annotation of mammalian phenotypes in the context of mutations, quantitative trait loci and strains that are used as models of human biology and disease. The MP Ontology supports different levels and richness of phenotypic knowledge and flexible annotations to individual genotypes. It continues to develop dynamically via collaborative input from research groups, mutagenesis consortia, and biological domain experts. The MP Ontology is currently used by the Mouse Genome Database and Rat Genome Database to represent phenotypic data.

Epidemiological studies reveal increased incidence of lung infection when air pollution particle levels are increased. We postulate that one risk factor for bacterial pneumonia, prior viral infection, can prime the lung for greater deleterious effects of particles via the interferon-gamma (IFN-gamma) characteristic of successful host anti-viral responses. To test this postulate, we developed a mouse model in which mice were treated with gamma-interferon aerosol, followed by exposure to concentrated ambient particles (CAPs) collected from urban air. The mice were then infected with Streptococcus pneumoniae and the effect of these treatments on the lung's innate immune response was evaluated. The combination of IFN-gamma priming and CAPs exposure enhanced lung inflammation, manifest as increased polymorphonuclear granulocyte (PMN) recruitment to the lung, and elevated expression of pro-inflammatory cytokine mRNAs. Combined priming and CAPs exposure resulted in impaired pulmonary bacterial clearance, as well as increased oxidant production and diminished bacterial uptake by alveolar macrophages (AMs) and PMNs. The data suggest that priming and CAPs exposure lead to an inflamed alveolar milieu where oxidant stress causes loss of antibacterial functions in AMs and recruited PMNs. The model reported here will allow further analysis of priming and CAPs exposure on lung sensitivity to infection.

The role of air pollution in the initiation of asthma is controversial. We sought to model the potential effects of air pollution on immune responses to inhaled allergens in developing lungs by using very young mice. Neonatal mice were repeatedly exposed to aerosolized ovalbumin (OVA; 3% in phosphate-buffered saline for 10 min/d, from Days 5 to 15 of age). Some mice were also exposed to leachate of residual oil fly ash (ROFA-s), a surrogate for ambient air particles, for 30 min, on Days 6, 8, and 10 of age). Repeated exposure of very young mice to allergen alone (OVA) or pollutant alone (ROFA-s) had no effect on airway hyperresponsiveness (AHR, measured as enhanced pause (Penh) with noninvasive plethysmography at Day 16 of age), and did not cause inflammation or OVA-specific antibody production. Similar exposures of adult mice to either OVA alone or to OVA + ROFA-s did result in AHR, without evidence of enhancement by combined exposure. In contrast, very young mice exposed to both OVA and ROFA-s showed significantly increased AHR (e.g., Penh with 50 mg/ml methacholine for OVA + ROFA-s versus OVA alone = 2.6 +/- 0.4 [mean +/- SE], versus 1.2 +/- 0.1; p < 0.01, n >/= 15), and produced OVA-specific IgE and IgG upon allergen challenge a week later. Immunostaining of airways taken from mice at Day 11 showed a marked increase in Ia(+) cells after OVA + ROFA-s exposure. We conclude that exposure to pollutant aerosols can disrupt normal resistance to sensitization to inhaled allergens, and can thereby promote development of airway hypersensitivity in this neonatal/juvenile mouse model.

The treatment of schizophrenia has frustrated clinicians for over 50 years. Despite advances in neurotransmitter identification and the development of drugs targeting these transmitters, total remission of the disease is not always achieved. Potential etiologies other than neurotransmitter dysfunction merit consideration. One intriguing concept is the possible contribution of autoimmunity in patients with the disease. This breakdown of self-tolerance has been implicated in patients with other chronic diseases, such as type 1 diabetes mellitus and myasthenia gravis. The literature on autoimmunity as a possible mechanism in the pathogenesis of schizophrenia can be conflicting, but there is a substantial amount of circumstantial, although not conclusive, evidence of immune dysfunction in patients with schizophrenia.

The link between exposure to air pollution and exacerbation of asthma symptoms has been investigated by epidemiological study and by direct biological experimentation. In asthmatics, epidemiological studies generally show a positive correlation between the particulate fraction of air pollution and increased morbidity, although roles for other co-pollutants (for example, ozone) are implicated as well. Direct experimentation using air pollutants, especially particles, to investigate their effects on humans or on animal models of asthma provides corroboration of the epidemiology and has begun to identify the pathophysiological mechanisms involved. We begin this review with an overview of air pollution, followed by a survey of the epidemiological and experimental data regarding air pollution particles and asthma. We finish with a discussion of directions for future research.

We applied flow cytometric analysis to characterize the in vitro response of alveolar macrophages (AM) to air pollution particulates. Normal hamster AM were incubated with varying concentrations of residual oil fly ash (ROFA) or concentrated ambient air particulates (CAP). We found a dosedependent increase in AM-associated right angle light scatter (RAS) after uptake of ROFA (e.g., mean channel number 149.4 ± 6.5, 102.5 ± 4.1, 75.8 ± 3.5, and 61 .0 ± 4.6 at 200, 100, 50, and 25 mg/ml, respectively) or CAP. A role for scavenger-type receptors (SR) in AM uptake of components of ROFA and CAP was identified by marked inhibition of RAS increases in AM pretreated with the specific SR inhibitor polyinosinic acid. We combined measurement of particle uptake (RAS) with flow cytometric analysis of intracellular oxidation of dichlorofluorescin. Both ROFA and CAP caused a dose-related intracellular oxidant stress within AM, comparable to that seen with phorbol myristate acetate (PMA) (e.g., fold increase over control, 6.6±0.4, 3.6±0.4, 4.6 ± 0.5, 200 mg/ml ROFA, 100 mg/ml ROFA, and 10-7 M PMA, respectively). We conclude that flow cytometry of RAS increases provides a useful relative measurement of AM uptake of complex particulates within ROFA and CAP. Both ROFA and CAP cause substantial intracellular oxidant stress within AM, which may contribute to subsequent cell activation and production of proinflammatory mediators.

We applied flow cytometric analysis to characterize the in vitro response of alveolar macrophages (AM) to air pollution particulates. Normal hamster AM were incubated with varying concentrations of residual oil fly ash (ROFA) or concentrated ambient air particulates (CAP). We found a dosedependent increase in AM-associated right angle light scatter (RAS) after uptake of ROFA (e.g., mean channel number 149.4 ± 6.5, 102.5 ± 4.1, 75.8 ± 3.5, and 61 .0 ± 4.6 at 200, 100, 50, and 25 mg/ml, respectively) or CAP. A role for scavenger-type receptors (SR) in AM uptake of components of ROFA and CAP was identified by marked inhibition of RAS increases in AM pretreated with the specific SR inhibitor polyinosinic acid. We combined measurement of particle uptake (RAS) with flow cytometric analysis of intracellular oxidation of dichlorofluorescin. Both ROFA and CAP caused a dose-related intracellular oxidant stress within AM, comparable to that seen with phorbol myristate acetate (PMA) (e.g., fold increase over control, 6.6±0.4, 3.6±0.4, 4.6 ± 0.5, 200 mg/ml ROFA, 100 mg/ml ROFA, and 10-7 M PMA, respectively). We conclude that flow cytometry of RAS increases provides a useful relative measurement of AM uptake of complex particulates within ROFA and CAP. Both ROFA and CAP cause substantial intracellular oxidant stress within AM, which may contribute to subsequent cell activation and production of proinflammatory mediators.

Over the last six decades, the treatment of schizophrenia has focused primarily on interactions at monoamine neurotransmitter receptor sites, including those for dopamine and serotonin. While first-generation antipsychotics demonstrate antagonism at the dopamine 2 receptor, newer atypical agents involve multiple receptors at various neurotransmitter sites. Despite the advent of these newer agents, the treatment of schizophrenia continues to elude clinicians, perhaps owing to a lack of information about the factors contributing to the development of the disease. While the etiology is complex and not yet fully delineated, we suggest that treating clinicians be willing to look beyond neurotransmitters and entertain other potential factors involved in the pathogenesis of schizophrenia. One such factor that is often overlooked is the possible contribution of autoimmunity to disease development in at least a subset of patients. In this article we make an argument for consideration of immune dysfunction in the development of schizophrenia and suggest future directions for the field.