Little is known about the impact of viral infections on lung matrix despite its important contribution to mechanical stability and structural support. The composition of matrix also indirectly controls inflammation by influencing cell adhesion, migration, survival, proliferation and differentiation. Hyaluronan is a significant component of the lung extracellular matrix and production and degradation must be carefully balanced. We have discovered an imbalance in hyaluronan production following resolution of a severe lung influenza virus infection, driven by hyaluronan synthase 2 from epithelial cells, endothelial cells and fibroblasts. Furthermore hyaluronan is complexed with inter-α-inhibitor heavy chains due to elevated TNF-stimulated gene 6 expression and sequesters CD44-expressing macrophages. We show that intranasal administration of exogenous hyaluronidase is sufficient to release inter-α-inhibitor heavy chains, reduce lung hyaluronan content and restore lung function. Hyaluronidase is already used to facilitate dispersion of co-injected materials in the clinic. It is therefore feasible that fibrotic changes following severe lung infection and inflammation could be overcome by targeting abnormal matrix production.

Uncontrolled severe asthma is characterized by the generation of allergen-responsive Th2/Th17 memory T cells in lymph nodes, their excessive cytokine production in lung tissue and consequent infiltration of eosinophils and neutrophils from the peripheral circulation. Understanding how and where a potent and selective PI3Kd inhibitor will be maximally efficacious is key to developing effective therapies for severe asthma. To elucidate the pharmacodynamic effects of our highly selective PI3Kd inhibitors on multiple targets of allergic airway inflammation, we compare topical and systemic drug exposures in chronic OVA/alum rats. In addition, we investigated the effect of PI3Kd inhibition on CD4 memory T cells in BAL fluid from the OVA specific, MHC class II restricted αβ T-cell receptor (TCR) OT.2 transgenic mice, by measuring the PI3Kd pathway signaling phosphorylation of S6 ribosomal protein (pS6RPSer235/236)). Therapeutic intervention in the rat OVA/alum model was achieved by dosing on day 20 within the lung challenge phase. Efficacy readouts on day 23 showed elevated Th2 cytokine and granulocyte chemokine levels in BAL, which were reduced dose dependently by PI3Kd inhibition by either route of administration. Consequent influx of eosinophils was also reduced to a comparable degree by either i.t. or i.v. drug. Our results in the OT.2 mice demonstrate the utility of pS6RPSer235/236 in CD4+ T cells as a target engagement marker reflecting PI3Kd activity. We also demonstrate the importance of exposure in systemic circulation, regardless of route of administration, to inhibit Th2 signaling and optimally drive efficacy in experimental asthma-related pathophysiology.

A common polymorphism of the type 2 deiodinase gene (Thr92Ala DIO2) was found to be associated with insulin resistance in a mixed Caucasian population. The aim of this study was to investigate the association of the Thr92Ala DIO2 variant to indices of insulin resistance in the Old Order Amish. A genotype-phenotype association study was performed at the research clinic in Strasburg, Pennsylvania, and the molecular genetics laboratory at the University of Maryland, Baltimore, Maryland, and the National Institutes of Health, Bethesda, Maryland. A total of 1,268 subjects participated in the Amish Family Diabetes Study. An association among the Thr92Ala DIO2 variant and type 2 diabetes, indices of insulin resistance (HOMA-IR), insulin secretion, free thyroid hormones, and thyrotropin (TSH) was found. No association was found among the Thr92Ala DIO2 variant and type 2 diabetes, impaired glucose tolerance, or body mass index (BMI) in the Amish. In nondiabetics (n = 747), the Ala92 allele tended to be associated with decreased rather then increased insulin secretion. No differences were observed in thyroid hormones or TSH. Contrary to prior findings, the Thr92Ala DIO2 variant tends to be associated with increased rather then decreased insulin sensitivity in the Amish. These findings could be secondary to a different genetic background or to environmental factors specific for this population.

Objective: The goal of this investigation was to determine in healthy adults the effect of expectation manipulations on the development of motion sickness, as indicated by abnormal gastric myoelectric activity and subjective reports of symptoms of motion sickness. Method: Eighty participants, moderately susceptible to motion sickness, experienced one of four conditions created from a two-variable (Expectation, Drum), two-factor model (High/Low expectation for sickness; Rotating/Stable Drum). The electrogastrogram (EGG) was recorded 6 min prior to the expectation manipulation; 6 min following the expectation manipulation; 6 min before drum activation; and 16 min during drum activation. Self-report questionnaires indicating expectation for sickness (MSEx) and motion sickness symptoms (Nausea Profile [NP]) were obtained following the expectation manipulation and exposure to the drum, respectively. Results: No significant differences were observed among expectation groups for retrospective reports of motion sickness (NP); however, significant differences in EGG responses to drum rotation were obtained. The unexpected results of a univariate analysis of variance (ANOVA) revealed significantly greater gastric tachyarrhythmia and less normal activity, an indication of motion sickness, in the low expectation for sickness conditions. Conclusion: These results suggest that inducing a high expectation for sickness in healthy individuals about to be exposed to provocative motion results in a protective effect from motion sickness following exposure to the stimulus, while low expectations may induce abnormal gastric activity.