Ozone impairs endogenous compensatory responses in allergic asthma.

Asthma is a chronic inflammatory airway disease characterized by acute exacerbations triggered by inhaled allergens, respiratory infections, or air pollution. Ozone (O3), a major component of air pollution, can damage the lung epithelium in healthy individuals. Despite this association, little is known about the effects of O3 and its impact on chronic lung disease. Epidemiological data have demonstrated that elevations in ambient O3 are associated with increased asthma exacerbations. To identify mechanisms by which O3 exposure leads to asthma exacerbations, we developed a two-hit mouse model where mice were sensitized and challenged with three common allergens (dust mite, ragweed and Aspergillus fumigates, DRA) to induce allergic inflammation prior to exposure to O3 (DRAO3). Changes in lung physiology, inflammatory cells, and inflammation were measured. Exposure to O3 following DRA significantly increased airway hyperreactivity (AHR), which was independent of TLR4. DRA exposure resulted in increased BAL eosinophilia while O3 exposure resulted in neutrophilia. Additionally, O3 exposure following DRA blunted anti-inflammatory and antioxidant responses. Finally, there were significantly less monocytes and innate lymphoid type 2 cells (ILC2s) in the dual challenged DRA-O3 group suggesting that the lack of these immune cells may influence O3-induced AHR in the setting of allergic inflammation. In summary, we developed a mouse model that mirrors some aspects of the clinical course of asthma exacerbations due to air pollution and identified that O3 exposure in the asthmatic lung leads to impaired endogenous anti-inflammatory and antioxidant responses and alterations inflammatory cell populations.

Effect of hypothyroidism on contractile performance of isolated end-stage failing human myocardium.

The relationship between hypothyroidism and the occurrence and progression of heart failure (HF) has had increased interest over the past years. The low T3 syndrome, a reduced T3 in the presence of normal thyroid stimulating hormone (TSH), and free T4 concentration, is a strong predictor of all-cause mortality in HF patients. Still, the impact of hypothyroidism on the contractile properties of failing human myocardium is unknown. Our study aimed to investigate that impact using ex-vivo assessment of force and kinetics of contraction/relaxation in left ventricular intact human myocardial muscle preparations. Trabeculae were dissected from non-failing (NF; n = 9), failing with no hypothyroidism (FNH; n = 9), and failing with hypothyroidism (FH; n = 9) hearts. Isolated muscle preparations were transferred into a custom-made setup where baseline conditions as well as the three main physiological modulators that regulate the contractile strength, length-dependent and frequency-dependent activation, as well as ß-adrenergic stimulation, were assessed under near-physiological conditions. Hypothyroidism did not show any additional significant impact on the contractile properties different from the recognized alterations usually detected in such parameters in any end-stage failing heart without thyroid dysfunction. Clinical information for FH patients in our study revealed they were all receiving levothyroxine. Absence of any difference between failing hearts with or without hypothyroidism, may possibly be due to the profound effects of the advanced stage of heart failure that concealed any changes between the groups. Still, we cannot exclude the possibility of differences that may have been present at earlier stages. The effects of THs supplementation such as levothyroxine on contractile force and kinetic parameters of failing human myocardium require further investigation to explore its full potential in improving cardiovascular performance and cardiovascular outcomes of HF associated with hypothyroidism.

Characterization of inflammatory changes in the breast cancer associated adipose tissue and comparison to the unaffected contralateral breast.

BACKGROUND: Adipose tissue has emerged as an important window into cancer pathophysiology, revealing potential targets for novel therapeutic interventions. The goal of this study was to compare the breast adipose tissue (BrAT) immune milieu surrounding breast carcinoma and contralateral unaffected breast tissue obtained from the same patient. MATERIALS AND METHODS: Patients undergoing bilateral mastectomy for unilateral breast cancer were enrolled for bilateral BrAT collection at the time of operation. After BrAT was processed, adipocyte and stromal vascular fraction (SVF) gene expression was quantified by PCR. SVF cells were also processed for flow cytometric immune cell characterization. RESULTS: Twelve patients underwent bilateral mastectomy for unilateral ductal carcinoma. BrAT adipocyte CXCL2 gene expression trended higher in the tumor-affected breast as compared to the unaffected breast. Macrophage MCP-1 and PPARγ gene expression also tended to be higher in the tumor-affected breasts. T cell gene expression of FOXP3 (p = 0.0370) were significantly greater in tumor-affected breasts than unaffected breasts. Affected BrAT contained higher numbers of Th2 CD4+ cells (p = 0.0165) and eosinophils (p = 0.0095) while trending towards increased macrophage and lower Th1 CD4+ cells infiltration than tumor-affected BrAT. CONCLUSION: This preliminary study aimed to identify the immunologic environment present within BrAT and is the first to directly compare this in individual patients' tumor-associated and unaffected BrAT. These findings suggest that cancer-affected BrAT had increased levels of T cell specific FOXP3 and higher levels of anti-inflammatory/regulatory cells compared to the contralateral BrAT.