Background: Bronchopulmonary dysplasia (BPD) is a serious lung disease caused by oxidative stress, predominately affecting premature infants that require prolonged oxygen support. The co-factor flavin adenine dinucleotide (FADH) facilitates glutathione reductase (GR) enzymatic activity and increases the bioavailability of the antioxidant glutathione (GSH). As such, we hypothesized that intranasal delivery of FADH can improve redox homeostasis and attenuate lung injury following chronic high oxygen supplementation (0.85% FiO2) by altering pro-inflammatory signal transduction pathways in a C57Bl6 newborn mouse model for BPD. Methods: We used a prolonged hyperoxia-induced lung injury rodent model to recapitulate the clinical and histological changes present in BPD. Newborn mice were housed in FiO2 85% (hyperoxic) or 21% O2 (normoxic) from day of birth until post-natal day (PN) 14. FADH (7 μM) or saline (control) treatments were administered daily via intranasal insufflation on PN 14-21 in a final volume of 1.5μL/g body weight. BALF and lung tissue samples were collected and evaluated for redox stress, lung injury/development, and inflammation using standard immunohistological techniques, morphometric analysis, and standard molecular assays. BALF cytokines were measured using a flow cytometric approach (BioLegend). Two-dimensional cell migration assays were tracked via microscopy daily until 100% confluence reached; the ½ maximal peak values were evaluated to compare rate of wound closure following very low (2.5 ng/mL) TNFα or IL12 treatment. Transepithelial resistance and potential differences were measured using an EVOM device (World Precision Instrument) across human small airway epithelial cells, and equivalent short circuit currents (Isc) calculated in accordance with Ohm’s Law, where V=IR. Single data comparisons were performed using paired Student’s t-tests. Multiple comparisons were performed using ANOVA followed by post-hoc testing in Sigma Plot. Results: FADH protected neonatal lungs from high oxygen induced oxidative stress: GSH/GSSG Eh (a measure of oxidative stress) improved from -168.77 mV ± 3.64 mV to -179.10 mV ± 1.85 mV (n=5 BALF measurements). FADH also improved lung injury scores from 0.187±0.038 to 0.03±0.014 (p=0.005), decreased neutrophil migration (p<0.001), and increased macrophages (p<0.001) when compared to age-matched untreated pups. FADH-mediated increase in TNFα (and not IL12) significantly increased the rate of lung epithelial cell wound closure from [2.27±0.07 to 1.97±0.1 average days for ½ complete wound closure, n=6, p=0.01] and increased Isc from 6.5±.21 to 9.2±1.0 μA/cm2, n=3, p=0.03. Conclusions: Our findings indicate that FADH protects the preterm lung from hyperoxic injury by 1) increasing the bioavailability of GSH and 2) via TNFα signaling to increase the rate of wound closure and repair of epithelial cell function. Significances: The mechanisms identified through this study could be targeted as a potential adjunct therapy for BPD patients to attenuate high oxygen induced lung injury. Funding: Supported by R01HL137033 (MH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background: Bronchopulmonary dysplasia (BPD) is a severe oxidative-stress induced lung disease that primarily affects premature infants requiring long term oxygen supplementation. BPD is characterized by attenuated lung development, fibrosis, inflammation, and airway smooth muscle hyperplasia. Our research objective was to test a novel hypothesis that evaluates whether providing flavin adenine dinucleotide (FADH) can reduce oxidative stress and prevent high oxygen induced lung injury using a mouse model for BPD. FADH is a cofactor for glutathione reductase (GR) enzymatic activity, responsible for recycling the bioavailability of the antioxidant glutathione (GSH) under oxidizing conditions. Methods: We used a hyperoxia-induced lung injury term mouse model (0.85 fraction inspired oxygen; FiO 2 ) to recapitulate the BPD phenotype for experimental study. Briefly, newborn mice were housed in 0.85 FiO 2 (hyperoxic) or 21% O 2 (normoxic) conditions from birth until post-natal day (PN) 14. Following O 2 exposures, FADH (7 μM) or vehicle (saline) treatments were insufflated daily on PN 14-21 (1.5μL/g body weight). Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected and evaluated for redox stress, lung injury/alveolar development, and inflammation using commercially available GSH Assay kits (Abcam), standard immunohistochemistry, and LEGENDplex inflammation panels (Biolegend), respectively. Male and female mice were randomly assigned to study groups. Single data comparisons were performed using paired Student’s t-tests. Multiple comparisons were performed using one-way analysis of variance followed by post-hoc testing in Sigma Plot (SPSS Inc). Results: Daily insufflation of FADH improved neonatal lung health following chronic 0.85 FiO 2 exposure, as indicated by measured BALF GSH/GSSG redox potentials (E h ). E h = - 179.10 mV ± 1.85 mV in the FADH treated groups (n=5), wherein vehicle treated lungs were more oxidatively stressed with BALF E h = - 168.77 mV ± 3.64 mV (n=3 independent litters; P=.02). Morphometric analysis of lung development and lung injury scores were significantly improved in 0.85 FiO 2 exposed pups receiving FADH treatment vs. vehicle control pups ( P<.001; n=3 litters). FADH treatments also suppressed neutrophil infiltration (n=10; P<.001) with significant increase in IL-12p70 ( P<.05) and TNF-α ( P<.05; n=3 litters) in hyperoxic lungs. Conclusions: FADH protects the preterm lung from hyperoxic injury, albeit the mechanisms remain unclear. Importantly, we show that FADH increases the bioavailability of the antioxidant GSH, as well as IL12-p70 and TNF-α. The signaling molecules identified have known anti- and pro-inflammatory effects in the lungs and will therefore be explored in future studies as potential therapeutic targets involved in the pathogenesis of high-oxygen induced lung injury. Supported by T35DK103596 (HM) and R01HL137033 (MH). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background. Hyperhemolysis syndrome (HS) is a severe hemolytic transfusion reaction that can cause hemoglobin and hematocrit levels to drop below pretransfusion levels, leading to severe anemia. HS most commonly occurs in patients with a pre-existing hemoglobinopathy such as sickle cell disease (SCD) or beta-thalassemia. Methods. We report a case of HS, occurring in the absence of hemoglobinopathy, making the diagnosis challenging. The patient reported was also affected by a CIC-rearranged sarcoma. As part of the workup, the patient received a bone marrow biopsy for suspected hemophagocytic lymphohistiocytosis. Results. This provided a rare biopsy specimen to correlate reticulocytopenia with marked erythroid hyperplasia in the marrow, supporting the hypothesis of reticulocyte destruction as a contributing cause of anemia in these patients. This patient had demonstrable alloantibodies to the Jk(a) and P1 antigens as potential triggers for HS. Conclusions. It is vital that a diagnosis of HS be correctly made in these patients with severe anemia, as blood transfusions generally lead to worsening of their conditions.

Azathioprine (AZA) is an immunosuppressant that is widely used to treat many disease states including rheumatoid arthritis. We present a patient who was treated with AZA for rheumatoid arthritis and subsequently hospitalized for severe myelosuppression due to acquired aplastic anemia. Upon genetic testing it was found that the patient was thiopurine methyltransferase (TMPT) deficient, a well-documented risk factor for myelosuppression in patients taking azathioprine. We advocate for TPMT and nudix hydrolase 15 (NUDT15) testing prior to initiation of AZA treatment, or close monitoring with a complete blood count post-AZA initiation to avoid these serious side effects.

Commuting accounts for one of the highest daily air pollution exposure periods for workers in the U.S.; however, exposures vary greatly depending on transportation mode. In this study, we compared commuters' (N = 433) perceived versus actual air pollution exposures across six modes of commuting in Salt Lake City, Utah. Commuter perceptions of exposure were compared with measured (actual) fine particulate matter (PM2.5) exposures. Comparisons were made using the Wilcoxon signed-rank test. Participants ranked active modes of commuting (walking and bicycling) as being less exposing to air pollution than automobile and public transportation modes, while actual exposures indicated that walking and bicycling yielded the highest exposures (p < .001). Our findings suggest the general public lacks an understanding of the factors that influence daily air pollution exposures during commuting. Public health programs could reduce commuters' lifetime exposures through education directed toward actions people can take to reduce daily inhaled doses of air pollution.

Background: Social capital is a construct of interaction and social trust in one’s fellow community members. These interactions can provide a safety net for individuals in terms of information, social support, and adherence to social norms. While a number of studies have previously examined the relationship between social capital and health outcomes, few have examined the theparallel relationship of social capital and geographic "place" with respect to health outcomes. Methods: Considering social capital as facilitated by specific structures, we evaluate the relationship between neighborhood-level social capital and disability rates in a major Southern US city. Disability rates were collected through neighborhood-level data via the AmericanCommunity Survey (ACS) and compared to a geocoded map of neighborhood-level social capital measures during spring, 2016. Results: Higher social capital within a neighborhood coincided with lower disability rates in that neighborhood (r=-0.14, P=0.016) when compared to random assortment models. Conclusion: Findings from this research add evidence to the value of the built environment, not only providing resources and shaping choices, but for facilitating important social relationships.