Long-term effects of prenatal arsenic exposure from gestational day 9 to birth on lung, heart, and immune outcomes in the C57BL/6 mouse model.

Prenatal arsenic exposure is a major public health concern, associated with altered birth outcomes and increased respiratory disease risk. However, characterization of the long-term effects of mid-pregnancy (second trimester) arsenic exposure on multiple organ systems is scant. This study aimed to characterize the long-term impact of mid-pregnancy inorganic arsenic exposure on the lung, heart, and immune system, including infectious disease response using the C57BL/6 mouse model. Mice were exposed from gestational day 9 till birth to either 0 or 1000 µg/L sodium (meta)arsenite in drinking water. Male and female offspring assessed at adulthood (10-12 weeks of age) did not show significant effects on recovery outcomes after ischemia reperfusion injury but did exhibit increased airway hyperresponsiveness compared to controls. Flow cytometric analysis revealed significantly greater total numbers of cells in arsenic-exposed lungs, lower MHCII expression in natural killer cells, and increased percentages of dendritic cell populations. Activated interstitial (IMs) and alveolar macrophages (AMs) isolated from arsenic-exposed male mice produced significantly less IFN-γ than controls. Conversely, activated AMs from arsenic-exposed females produced significantly more IFN-γ than controls. Although systemic cytokine levels were higher upon Mycobacterium tuberculosis (Mtb) infection in prenatally arsenic-exposed offspring there was no difference in lung Mtb burden compared to controls. This study highlights significant long-term impacts of prenatal arsenic exposure on lung and immune cell function. These effects may contribute to the elevated risk of respiratory diseases associated with prenatal arsenic exposure in epidemiology studies and point to the need for more research into mechanisms driving these maintained responses.

Metformin Alleviates Airway Hyperresponsiveness in a Mouse Model of Diet-Induced Obesity.

Obese asthma is a unique phenotype of asthma characterized by non-allergic airway hyperresponsiveness (AHR) and inflammation which responds poorly to standard asthma therapy. Metformin is an oral hypoglycemic drug with insulin-sensitizing and anti-inflammatory properties. The objective of the current study was to test the effect of metformin on AHR in a mouse model of diet-induced obesity (DIO). We fed 12-week-old C57BL/6J DIO mice with a high fat diet for 8 weeks and treated them with either placebo (control, n = 10) or metformin (n = 10) added in drinking water (300 mg/kg/day) during the last 2 weeks of the experiment. We assessed AHR, metabolic profiles, and inflammatory markers after treatments. Metformin did not affect body weight or fasting blood glucose, but significantly reduced serum insulin (p = 0.0117). Metformin reduced AHR at 30 mg/ml of methacholine challenge (p = 0.0052) without affecting baseline airway resistance. Metformin did not affect circulating white blood cell counts or lung cytokine mRNA expression, but modestly decreased circulating platelet count. We conclude that metformin alleviated AHR in DIO mice. This finding suggests metformin has the potential to become an adjuvant pharmacological therapy in obese asthma.

Caloric restriction prevents the development of airway hyperresponsiveness in mice on a high fat diet.

We have previously shown that high fat diet (HFD) for 2 weeks increases airway hyperresponsiveness (AHR) to methacholine challenge in C57BL/6J mice in association with an increase in IL-1ß levels in lung tissue. We hypothesize that obesity increases AHR via the IL-1ß mechanism, which can be prevented by caloric restriction and IL-1ß blockade. In this study, we fed C57BL/6J mice for 8 weeks with several hypercaloric diets, including HFD, HFD supplemented with fructose, high trans-fat diet (HTFD) supplemented with fructose, either ad libitum or restricting their food intake to match body weight to the mice on a chow diet (CD). We also assessed the effect of the IL-1ß receptor blocker anakinra. All mice showed the same total respiratory resistance at baseline. All obese mice showed higher AHR at 30 mg/ml of methacholine compared to CD and food restricted groups, regardless of the diet. Obese mice showed significant increases in lung IL-1 ß mRNA expression, but not the protein, compared to CD and food restricted mice. Anakinra abolished an increase in AHR. We conclude that obesity leads to the airway hyperresponsiveness preventable by caloric restriction and IL-1ß blockade.

High fat diet induces airway hyperresponsiveness in mice.

The experiment was conducted to examine the effect of a high fat diet (HFD) on airway hyperresponsiveness (AHR) in mice. Twenty-three adult male C57BL/6 J mice were fed with HFD or regular chow diet for two weeks. The total respiratory resistance was measured by forced oscillation technique at baseline and after methacholine aerosol challenge at 1, 3, 10 and 30 mg/mL. Bronchoalveolar lavage (BAL) was performed. Lipid levels and lipid peroxidation in lung tissue were measured along with gene expression of multiple cytokines. Lungs were digested, and IL-1ß secretion by pulmonary macrophages was determined. HFD feeding resulted in 11% higher body weight compared to chow. HFD did not affect respiratory resistance at baseline, but significantly augmented airway responses to methacholine compared to chow diet (40.5 ± 17.7% increase at 30 mg/ml methacholine, p < 0.05). HFD induced a 3.2 ± 0.6 fold increase in IL-1ß gene expression (p < 0.001) and a 38 fold increase in IL-1ß secretion in the lungs. There was no change in BAL and no change in any other cytokines, lipid levels or lipid peroxidation. Hence, HFD induced AHR in mice prior to the development of significant obesity which was associated with up-regulation of pulmonary IL-1ß.