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Introduction Acute exposure to carbon dioxide ([CO.sub.2]) is considered non-toxic at levels up to at least the Occupational Safety and Health Administration Permissible Exposure Limit of 5,000 ppm. However, at [...]

Macrophages play a key role in ozone-induced lung injury by regulating both the initiation and resolution of inflammation. These distinct activities are mediated by pro-inflammatory and anti-inflammatory/proresolution macrophages which sequentially accumulate in injured tissues. Macrophage activation is dependent, in part, on intracellular metabolism. Herein, we used RNA-sequencing (seq) to identify signaling pathways regulating macrophage immunometabolic activity following exposure of mice to ozone (0.8 ppm, 3 h) or air control. Analysis of lung macrophages using an Agilent Seahorse showed that inhalation of ozone increased macrophage glycolytic activity and oxidative phosphorylation at 24 and 72 h post-exposure. An increase in the percentage of macrophages in S phase of the cell cycle was observed 24 h post ozone. RNA-seq revealed significant enrichment of pathways involved in innate immune signaling and cytokine production among differentially expressed genes at both 24 and 72 h after ozone, whereas pathways involved in cell cycle regulation were upregulated at 24 h and intracellular metabolism at 72 h. An interaction network analysis identified tumor suppressor 53 (TP53), E2F family of transcription factors (E2Fs), cyclin-dependent kinase inhibitor 1A (CDKN1a/p21), and cyclin D1 (CCND1) as upstream regulators of cell cycle pathways at 24 h and TP53, nuclear receptor subfamily 4 group a member 1 (NR4A1/Nur77), and estrogen receptor alpha (ESR1/ERα) as central upstream regulators of mitochondrial respiration pathways at 72 h. To assess whether ERα regulates metabolic activity, we used ERα−/− mice. In both air and ozone-exposed mice, loss of ERα resulted in increases in glycolytic capacity and glycolytic reserve in lung macrophages with no effect on mitochondrial oxidative phosphorylation. Taken together, these results highlight the complex interaction between cell cycle, intracellular metabolism, and macrophage activation which may be important in the initiation and resolution of inflammation following ozone exposure. [ABSTRACT FROM AUTHOR]

Recent studies have identified exposure to environmental levels of ozone as a risk factor for the development of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) that can develop in humans with sepsis. The aim of this study was to develop a murine model of ALI to mechanistically explore the impact of ozone exposure on ARDS development. Mice were exposed to ozone (0.8 ppm, 3 h) or air control followed 24 h later by intravenous administration of 3 mg/kg lipopolysaccharide (LPS) or PBS. Exposure of mice to ozone + LPS caused alveolar hyperplasia; increased BAL levels of albumin, IgM, phospholipids, and proinflammatory mediators including surfactant protein D and soluble receptor for advanced glycation end products were also detected in BAL, along with markers of oxidative and nitrosative stress. Administration of ozone + LPS resulted in an increase in neutrophils and anti-inflammatory macrophages in the lung, with no effects on proinflammatory macrophages. Conversely, the numbers of resident alveolar macrophages decreased after ozone + LPS; however, expression of Nos2 , Arg1 , Cxcl1 , Cxcl2 , Ccl2 by these cells increased, indicating that they are activated. These findings demonstrate that ozone sensitizes the lung to respond to endotoxin, resulting in ALI, oxidative stress, and exacerbated pulmonary inflammation, and provide support for the epidemiologic association between ozone exposure and ARDS incidence. [ABSTRACT FROM AUTHOR]

Aim: Chronotype reflects a circadian rhythmicity that regulates endothelial function. While the morning chronotype (MORN) usually has low cardiovascular disease risk, no study has examined insulin action on endothelial function between chronotypes. We hypothesized intermediate chronotypes (INT) would have lower vascular insulin sensitivity than morning chronotype (MORN). Materials and Methods: Adults with obesity were classified per Morningness‐Eveningness Questionnaire (MEQ) as either MORN (n = 27, 22 female, MEQ = 63.7 ± 4.7, 53.8 ± 6.7 years, 35.3 ± 4.9 kg/m2) or INT (n = 29, 23 female, MEQ = 48.8 ± 6.7, 56.6 ± 9.0 years, 35.7 ± 6.1 kg/m2). A 120 min euglycaemic‐hyperinsulinaemic clamp (40 mU/m2/min, 90 mg/dl) was conducted to assess macrovascular insulin sensitivity via brachial artery flow‐mediated dilation (%FMD; conduit artery), post‐ischaemic flow velocity (resistance arteriole), as well as microvascular insulin sensitivity via contrast‐enhanced ultrasound [e.g. microvascular blood volume (perfusion)]. Fasting plasma arginine and citrulline, as well as fasting and clamp‐derived plasma endothelin‐1 and nitrate/nitrite, were assessed as surrogates of vasoconstriction and nitric oxide‐mediated vasodilation. Aerobic fitness (VO2max) and body composition (dual‐energy X‐ray absorptiometry) were also collected. Results: MORN had a higher VO2max compared with INT (p <.01), although there was no difference in fat mass. While fasting FMD was similar between groups, insulin lowered FMD corrected to shear stress and microvascular blood volume in INT compared with MORN after co‐varying for VO2max (both p ≤.02). INT also had a lower fasting nitrate (p =.03) and arginine (p =.07). Higher MEQ correlated with elevated FMD (r = 0.33, p =.03) and lower post‐ischaemic flow velocity (r = −0.33, p =.03) as well as shear rate (r = −0.36, p =.02) at 120 min. Conclusion: When measured during the morning, INT had a lower vascular insulin sensitivity than MORN. Additional work is needed to understand endothelial function differences among chronotypes to optimize cardiovascular disease risk reduction. [ABSTRACT FROM AUTHOR]

Exaggerated exercise blood pressure (BP) is linked to cardiovascular disease (CVD). Although evening chronotypes have greater CVD risk than morning (Morn) types, it is unknown if exercise BP differs in intermediate (Int) types. Adults with obesity were classified as either Morn [n = 23 (18 females), Morning-Eveningness Questionnaire (MEQ) = 63.96 ± 1.0, 54.74 ± 1.4 yr, 33.7 ± 0.6 kg/m²] or Int [n = 23 (19 females), MEQ = 51.36 ± 1.1, 55.96 ± 1.8 yr, 37.2 ± 1.2 kg/m²] chronotype per MEQ. A graded, incremental treadmill test to maximal aerobic capacity (VO2max) was conducted. Systolic (SBP) and diastolic (DBP) blood pressure and mean arterial pressure (MAP), rate pressure product (RPP), heart rate (HR), and rate of perceived intensity (RPE) were determined at baseline, 4 min, 6 min, and maximal stages. HR recovery (HRR; maximum postexercise) was determined at 1 and 2 min postexercise. Preexercise fasted aortic waveforms (applanation tonometry), plasma leptin, nitrate/nitrite (nitric oxide bioavailability), and body composition (dual X-ray, DXA) were also collected. Int had lower VO2max and plasma nitrate (both P ≤ 0.02) than Morn. No difference in preexercise BP, aortic waveforms, or body composition were noted between groups, although higher plasma leptin was seen in Int compared with Morn (P = 0.04). Although Int had higher brachial DBP and MAP across exercise stages (both P ≤ 0.05) and higher HR, RPE, and RPP at 6 min of exercise (all P ≤ 0.05), covarying for VO2max nullified the BP, but not HR or RPE, difference. HRR was greater in Morn independent of VO2max (P = 0.046). Fasted leptin correlated with HR at exercise stage 4 (r = 0.421, P = 0.041) and 6 min (r = 0.593, P = 0.002). This observational study suggests that Int has exaggerated BP and HR responses to exercise compared with Morn, although fitness abolished BP differences. [ABSTRACT FROM AUTHOR]

Exposure to ozone causes decrements in pulmonary function, a response associated with alterations in lung lipids. Pulmonary lipid homeostasis is dependent on the activity of peroxisome proliferator activated receptor gamma (PPARγ), a nuclear receptor that regulates lipid uptake and catabolism by alveolar macrophages (AMs). Herein, we assessed the role of PPARγ in ozone-induced dyslipidemia and aberrant lung function in mice. Exposure of mice to ozone (0.8 ppm, 3 h) resulted in a significant reduction in lung hysteresivity at 72 h post exposure; this correlated with increases in levels of total phospholipids, specifically cholesteryl esters, ceramides, phosphatidylcholines, phosphorylethanolamines, sphingomyelins, and di- and triacylglycerols in lung lining fluid. This was accompanied by a reduction in relative surfactant protein-B (SP-B) content, consistent with surfactant dysfunction. Administration of the PPARγ agonist, rosiglitazone (5 mg/kg/day, i.p.) reduced total lung lipids, increased relative amounts of SP-B, and normalized pulmonary function in ozone-exposed mice. This was associated with increases in lung macrophage expression of CD36, a scavenger receptor important in lipid uptake and a transcriptional target of PPARγ. These findings highlight the role of alveolar lipids as regulators of surfactant activity and pulmonary function following ozone exposure and suggest that targeting lipid uptake by lung macrophages may be an efficacious approach for treating altered respiratory mechanics. [ABSTRACT FROM AUTHOR]

E-cigarette consumption is under scrutiny by regulatory authorities due to concerns about product toxicity, lack of manufacturing standards, and increasing reports of e-cigarette- or vaping-associated acute lung injury. In vitro studies have demonstrated cytotoxicity, mitochondrial dysfunction, and oxidative stress induced by unflavored e-cigarette aerosols and flavoring additives. However, e-cigarette effects on the complex lung parenchyma remain unclear. Herein, the impact of e-cigarette condensates with or without menthol flavoring on functional, structural, and cellular responses was investigated using mouse precision cut lung slices (PCLS). PCLS were exposed to e-cigarette condensates prepared from aerosolized vehicle, nicotine, nicotine + menthol, and menthol e-fluids at doses from 50 to 500 mM. Doses were normalized to the glycerin content of vehicle. Video-microscopy of PCLS revealed impaired contractile responsiveness of airways to methacholine and dampened ciliary beating following exposure to menthol-containing condensates at concentrations greater than 300 mM. Following 500 mM menthol-containing condensate exposure, epithelial exfoliation in intrabronchial airways was identified in histological sections of PCLS. Measurement of lactate dehydrogenase release, mitochondrial water-soluble-tetrazolium salt-1 conversion, and glutathione content supported earlier findings of nicotine or nicotine + menthol e-cigarette-induced dose-dependent cytotoxicity and oxidative stress responses. Evaluation of PCLS metabolic activity revealed dose-related impairment of mitochondrial oxidative phosphorylation and glycolysis after exposure to menthol-containing condensates. Taken together, these data demonstrate prominent mentholinduced pulmonary toxicity and impairment of essential physiological functions in the lung, which warrants concerns about e-cigarette consumer safety and emphasizes the need for further investigations of molecular mechanisms of toxicity and menthol effects in an experimental model of disease. [ABSTRACT FROM AUTHOR]

Erythrocyte precursors produce abundant [alpha]- and [beta]-globin proteins, which assemble with each other to form hemoglobin A (HbA), the major blood oxygen carrier. [alpha]Hb-stabilizing protein (AHSP) binds free [alpha] subunits [...]

Surfactant protein D (SP-D), a member of the collectin superfamily, modulates pulmonary inflammatory responses and innate immunity. Disruption of the SP-D gene in mice induces peribronchiolar inflammation, accumulation of large, foamy macrophages, increased bronchoalveolar lavage (BAL) phospholipid, and pulmonary emphysema. We hypothesized that absence of SP-D aggravates hyperoxia-induced injury. To test this, SP-D-deficient (SP-[D.sup.-/-]) and wild-type (SP-[D.sup.+/+]) mice were exposed to 80% or 21% oxygen. Paradoxically, during 14 days of hyperoxia, SP-[D.sup.-/-] mice had 100% survival vs. 30% in SP-[D.sup.+/+]. The survival advantage in SP-[D.sup.-/-] mice was accompanied by lower histopathological injury scores at days 5 and 14, although total BAL cells (8.2 [+ or -] 1.4 x [10.sup.5] in SP-[D.sup.-/-] vs. 4.04 [+ or -] 0.25 x [10.sup.5] in SP-[D.sup.+/+] mice) and neutrophils (1.2 [+ or -] 0.4 x [10.sup.5] vs. 0.03 [+ or -] 0.02 x [10.sup.5] in SP-[D.sup.-/-] and SP-[D.sup.+/+], respectively) were increased. In addition, BAL protein and lung-to-body weight ratios were similarly elevated in both groups after 3, 5, and 14 days of continuous exposure. Biochemically, in contrast to SP-[D.sup.+/+], SP-[D.sup.-/-] mice had higher levels of surfactant phospholipid and SP-B at baseline and 5 days after hyperoxia accompanied by a preservation of surfactant biophysical activity. From a multiplex assay of nine cytokines, we found elevated levels of IL-13 in BAL fluid of normoxic SP-[D.sup.-/-] mice compared with SP-[D.sup.+/+]. We conclude that the resistance of SP-D-deficient mice to hyperoxia reflects homeostatic changes in the SP-[D.sup.-/-] phenotype involving both phospholipid and SP-B-mediated induced resistance of surfactant to inactivation as well as changes in the immunomodulatory BAL cytokine profile. surfactant protein D; inflammation; alveolar macrophages; collectin