Pulmonary arterial remodeling induced by a Th2 immune response

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH

Prenatal allergen and diesel exhaust exposure and their effects on allergy in adult offspring mice

Multiple studies have suggested that prenatal exposure to either allergens or air pollution may increase the risk for the development of allergic immune responses in young offspring. However, the effects of prenatal environmental exposures on adult offspring have not been well-studied. We hypothesized that combined prenatal exposure to Aspergillus fumigatus (A. fumigatus) allergen and diesel exhaust particles will be associated with altered IgE production, airway inflammation, airway hyperreactivity (AHR), and airway remodeling of adult offspring. Following sensitization via the airway route to A. fumigatus and mating, pregnant BALB/c mice were exposed to additional A. fumigatus and/or diesel exhaust particles. At age 9-10 weeks, their offspring were sensitized and challenged with A. fumigatus. We found that adult offspring from mice that were exposed to A. fumigatus or diesel exhaust particles during pregnancy experienced decreases in IgE production. Adult offspring of mice that were exposed to both A. fumigatus and diesel exhaust particles during pregnancy experienced decreases in airway eosinophilia. These results suggest that, in this model, allergen and/or diesel administration during pregnancy may be associated with protection from developing systemic and airway allergic immune responses in the adult offspring

Circulating MicroRNA Markers for Pulmonary Hypertension in Supervised Exercise Intervention and Nightly Oxygen Intervention

Rationale: Therapeutic exercise training has been shown to significantly improve pulmonary hypertension (PH), including 6-min walking distance and right heart function. Supplemental nightly oxygen also has therapeutic effects. A biomarker tool that could query critical gene networks would aid in understanding the molecular effects of the interventions.Methods: Paired bio-banked serum (n = 31) or plasma (n = 21) samples from the exercise or oxygen intervention studies, respectively, and bio-banked plasma samples (n = 20) from high altitude induced PH in cattle were tested. MicroRNAs (miRNAs) markers were chosen for study because they regulate gene expression, control the function of specific gene networks, and are conserved across species.Results: miRNAs that control muscle (miR-22-3p, miR-21-5p) or erythrocyte function (miR-451a) were chosen based on pilot experiments. Plasma samples from cattle that developed PH in high altitude had significantly higher miR-22-3p/(relative to) miR-451a values when compared to control cattle tolerant to high altitude. Measurements of miR-22-3p/miR-451a values in serum from patients receiving exercise training showed that the values were significantly decreased in 74.2% of the samples following intervention and significantly increased in the remainder (25.8%). In samples obtained after exercise intervention, a higher composite miRNA value, made of miR-22-3p and miR-21-5p/miR-451a and spike RNA, was significantly decreased in 65% of the samples and significantly increased in 35% of the samples. In the study of nightly oxygen intervention, when comparing placebo and oxygen, half of the samples showed a significant down-ward change and the other half a significant up-ward change measuring either of the miRNA markers. Samples that had a downward change in the miRNA marker following either intervention originated from patients who had a significantly higher 6-min-walking-distance at baseline (mean difference of 90 m or 80 m following exercise or oxygen intervention, respectively) when compared to samples that had an upward change in the miRNA marker.Conclusion: These natural animal model and human sample studies further highlight the utility of miRNAs as future biomarkers. The different directional changes of the miRNA markers following supervised exercise training or nightly oxygen intervention could indicate different PAH molecular pathomechanisms (endotypes). Further studies are needed to test this idea

Image_1_Circulating MicroRNA Markers for Pulmonary Hypertension in Supervised Exercise Intervention and Nightly Oxygen Intervention.JPEG

<p>Rationale: Therapeutic exercise training has been shown to significantly improve pulmonary hypertension (PH), including 6-min walking distance and right heart function. Supplemental nightly oxygen also has therapeutic effects. A biomarker tool that could query critical gene networks would aid in understanding the molecular effects of the interventions.</p><p>Methods: Paired bio-banked serum (n = 31) or plasma (n = 21) samples from the exercise or oxygen intervention studies, respectively, and bio-banked plasma samples (n = 20) from high altitude induced PH in cattle were tested. MicroRNAs (miRNAs) markers were chosen for study because they regulate gene expression, control the function of specific gene networks, and are conserved across species.</p><p>Results: miRNAs that control muscle (miR-22-3p, miR-21-5p) or erythrocyte function (miR-451a) were chosen based on pilot experiments. Plasma samples from cattle that developed PH in high altitude had significantly higher miR-22-3p/(relative to) miR-451a values when compared to control cattle tolerant to high altitude. Measurements of miR-22-3p/miR-451a values in serum from patients receiving exercise training showed that the values were significantly decreased in 74.2% of the samples following intervention and significantly increased in the remainder (25.8%). In samples obtained after exercise intervention, a higher composite miRNA value, made of miR-22-3p and miR-21-5p/miR-451a and spike RNA, was significantly decreased in 65% of the samples and significantly increased in 35% of the samples. In the study of nightly oxygen intervention, when comparing placebo and oxygen, half of the samples showed a significant down-ward change and the other half a significant up-ward change measuring either of the miRNA markers. Samples that had a downward change in the miRNA marker following either intervention originated from patients who had a significantly higher 6-min-walking-distance at baseline (mean difference of 90 m or 80 m following exercise or oxygen intervention, respectively) when compared to samples that had an upward change in the miRNA marker.</p><p>Conclusion: These natural animal model and human sample studies further highlight the utility of miRNAs as future biomarkers. The different directional changes of the miRNA markers following supervised exercise training or nightly oxygen intervention could indicate different PAH molecular pathomechanisms (endotypes). Further studies are needed to test this idea.</p

Inhibition of Acid-induced Lung Injury by Hyperosmolar Sucrose in Rats

Rationale: Acid aspiration causes acute lung injury (ALI). Recently, we showed that a brief intravascular infusion of hyperosmolar sucrose, given concurrently with airway acid instillation, effectively blocks the ensuing ALI

Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene.

Hypomorphic mutations in the bone morphogenic protein receptor (BMPR2) confer a much greater risk for developing pulmonary arterial hypertension (PAH). However, not all carriers of a mutation in the BMPR2 gene suffer from PAH. We have previously shown that prolonged T helper 2 (Th2) responses in the lungs to a mild antigen delivered via the airways induce severe pulmonary arterial remodeling, but no pulmonary hypertension. The current studies were designed to test the idea that Th2 responses to a mild antigen together with the expression of a hypomorphic BMPR2 gene would trigger pulmonary hypertension.Mice that expressed a hypomorphic BMPR2 transgene (transgene-positive) and transgene-negative mice were either exposed to saline, or primed and exposed to a mild antigen (Ovalbumin) over a prolonged period of time. Only transgene-positive but not transgene-negative mice exposed to antigen developed significantly increased right ventricular systolic pressures, while both groups showed pulmonary artery remodeling with severe muscularization and airway inflammation to a similar degree. Antigen exposure resulted in a smaller increase in the percentage of Interleukin (IL)-13 positive T cells in the lymph nodes, and in a smaller increase in resistin-like-molecule (RELM)α expression and a decreased ratio of expression of IL-33 relative to its receptor (IL-1-receptor-like 1, IL1RL1-ST2) in the right ventricles of transgene-positive mice compared to transgene-negative animals. Furthermore, only antigen-challenged transgene-positive mice showed a significant increase in Interferon (IFN)γ positive T cells over saline-exposed controls.Our study suggests that exposure with a mild Th2 antigen can trigger pulmonary hypertension on the background of the expression of a hypomorphic BMPR2 gene and that conversely, the expression of the hypomorphic BMPR2 gene can alter the immune response to a mild, inhaled antigen

Blimp-1 Attenuates Th1 Differentiation by Repression of ifng

T cell-specific deletion of Blimp-1 causes abnormal T cell homeostasis and function, leading to spontaneous, fatal colitis in mice. Herein we explore the role of Blimp-1 in Th1/Th2 differentiation. Blimp-1 mRNA and protein are more highly expressed in Th2 cells compared with Th1 cells, and Blimp-1 attenuates IFN-gamma production in CD4 cells activated under nonpolarizing conditions. Although Blimp-1-deficient T cells differentiate normally to Th2 cytokines in vitro, Blimp-1 is required in vivo for normal Th2 Immoral responses to NP-KLH (4-hydroxy-3-nitrophenylacetyl/keyhole lymphocyte hemocyanin) immunization. Lack of Blimp-1 in CD4 T cells causes increased IFN-gamma, T-bet, and Bcl-6 mRNA. By chromatin immunoprecipitation we show that Blimp-1 binds directly to a distal regulatory region in the ifng gene and at multiple sites in tbx21 and bcl6 genes. Our data provide evidence that Blimp-1 functions in Th2 cells to reinforce Th2 differentiation by repressing critical Th1 genes

Severe Acute Respiratory Syndrome and Particulate Matter Exposure: A Systematic Review

Background: Particulate matter (PM) exposure is responsible for seven million deaths annually and has been implicated in the pathogenesis of respiratory infections such as severe acute respiratory syndrome (SARS). Understanding modifiable risk factors of high mortality, resource burdensome C19 and exposure risks such as PM is key to mitigating their devastating effects. This systematic review focuses on the literature available, identifying the spatial and temporal variation in the role of quantified PM exposure in SARS disease outcome and planning our future experimental studies. Methods: The systematic review utilized keywords adhered to the PRISMA guidelines. We included original human research studies in English. Results: Initial search yielded N = 906, application of eligibility criteria yielded N = 46. Upon analysis of risk of bias N = 41 demonstrated high risk. Studies found a positive association between elevated PM2.5, PM10 and SARS-related outcomes. A geographic and temporal variation in both PM and C19’s role was observed. Conclusion: C19 is a high mortality and resource intensive disease which devastated the globe. PM exposure is also a global health crisis. Our systematic review focuses on the intersection of this impactful disease-exposure dyad and understanding the role of PM is important in the development of interventions to prevent future spread of viral infections