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1.  Defense traits of larval Drosophila melanogaster exhibit genetically based tradeoffs against different species of parasitoids 
Populations of Drosophila melanogaster face significant mortality risks from parasitoid wasps that use species-specific strategies to locate and survive in hosts. We tested the hypothesis that parasitoids with different strategies select for alternative host defense characteristics and in doing so contribute to the maintenance of fitness variation and produce trade-offs among traits. We characterized defense traits of Drosophila when exposed to parasitoids with different host searching behaviors (Aphaereta sp. and Leptopilina boulardi). We used host larvae with different natural alleles of the gene Dopa decarboxylase (Ddc), a gene controlling the production of dopamine and known to influence the immune response against parasitoids. Previous population genetic analyses indicate that our focal alleles are maintained by balancing selection. Genotypes exhibited a trade-off between the immune response against Aphaereta sp. and the ability to avoid parasitism by L. boulardi. We also identified a trade off between the ability to avoid parasitism by L. boulardi and larval competitive ability as indicated by differences in foraging and feeding behavior. Genotypes differed in dopamine levels potentially explaining variation in these traits. Our results highlight the potential role of parasitoid biodiversity on host fitness variation and implicate Ddc as an antagonistic pleiotropic locus influencing larval fitness traits.
PMCID: PMC3590849  PMID: 23461325
adaptation; pleiotropy; parasitism; genetic variation; behavior; polymorphism
2.  Targeted Aerosolized Delivery of Ascorbate in the Lungs of Chlorine-Exposed Rats 
Chlorine (Cl2)-induced lung injury is a serious public health threat that may result from industrial and household accidents. Post-Cl2 administration of aerosolized ascorbate in rodents decreased lung injury and mortality. However, the extent to which aerosolized ascorbate augments depleted ascorbate stores in distal lung compartments has not been assessed.
We exposed rats to Cl2 (300 ppm for 30 min) and returned them to room air. Within 15–30 min postexposure, rats breathed aerosolized ascorbate and desferal or vehicle (mean particle size 3.3 μm) through a nose-only exposure system for 60 min and were euthanized. We measured the concentrations of reduced ascorbate in the bronchoalveolar lavage (BAL), plasma, and lung tissues with high-pressure liquid chromatography, protein plasma concentration in the BAL, and the volume of the epithelia lining fluid (ELF).
Cl2-exposed rats that breathed aerosolized vehicle had lower values of ascorbate in their BAL, ELF, and lung tissues compared to air-breathing rats. Delivery of aerosolized ascorbate increased reduced ascorbate in BAL, ELF, lung tissues, and plasma of both Cl2 and air-exposed rats without causing lung injury. Based on mean diameter of aerosolized particles and airway sizes we calculated that approximately 5% and 1% of inhaled ascorbate was deposited in distal lung regions of air and Cl2-exposed rats, respectively. Significantly higher ascorbate levels were present in the BAL of Cl2-exposed rats when aerosol delivery was initiated 1 h post-Cl2.
Aerosol administration is an effective, safe, and noninvasive method for the delivery of low molecular weight antioxidants to the lungs of Cl2-exposed individuals for the purpose of decreasing morbidity and mortality. Delivery is most effective when initiated 1 h postexposure when the effects of Cl2 on minute ventilation subside.
PMCID: PMC3552173  PMID: 22393907
epithelial lining fluid; bronchoalveolar lavage; lung injury; HPLC; urea
3.  Post Chlorine gas exposure administration of nitrite prevents lung injury: effect of administration modality 
Free radical biology & medicine  2012;53(7):1431-1439.
Cl2 gas toxicity is complex and occurs during, and post exposure leading to acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl2 exposure can occur in diverse situations encompassing mass casualty scenarios underscoring the need for post-exposure therapies that are efficacious and amenable to rapid and easy administration. In this study, we compared the efficacy of a single dose, post (30min) Cl2 exposure administration of nitrite (1mg/kg) via intraperitoneal (IP) or intramuscular (IM) injection in rats, to decrease ALI. Exposure of rats to Cl2 gas (400ppm, 30min) significantly increased ALI and caused RAS 6–24h post exposure as indexed by BAL sampling of lung surface protein, PMN and increased airway resistance and elastance prior to and post methacholine challenge. IP nitrite decreased Cl2 - dependent increases in BAL protein but not PMN. In contrast IM nitrite decreased BAL PMN levels without decreasing BAL protein in a xanthine oxidoreductase independent manner. Histological evaluation of airways 6h post exposure showed significant bronchial epithelium exfoliation and inflammatory injury in Cl2 exposed rats. Both IP and IM nitrite improved airway histology compared to Cl2 gas alone, but more coverage of the airway by cuboidal or columnar epithelium was observed with IM compared to IP nitrite. Airways were rendered more sensitive to methacholine induced resistance and elastance after Cl2 gas exposure. Interestingly, IM nitrite, but not IP nitrite, significantly decreased airway sensitivity to methacholine challenge. Further evaluation and comparison of IM and IP therapy showed a two-fold increase in circulating nitrite levels with the former, which was associated with reversal of post-Cl2 exposure dependent increases in circulating leukocytes. Halving the IM nitrite dose resulted in no effect in PMN accumulation but significant reduction of of BAL protein levels indicating distinct nitrite dose dependence for inhibition of Cl2 dependent lung permeability and inflammation. These data highlight the potential for nitrite as a post-exposure therapeutic for Cl2 gas induced lung injury and also suggest that administration modality is a key consideration in nitrite therapeutics.
PMCID: PMC3448851  PMID: 22917977
inhaled irritants; nitric oxide; inflammation; lung; nitrite
4.  On the Hydrophobicity of Nitrogen Dioxide: Could there be a “lens” effect for NO2 reaction kinetics? 
Solvent “lens” effects for the reaction kinetics of NO2 can be evaluated on the basis of published Henry’s law constants for nitrogen dioxide in various solvents. Water-to-organic solvent partition coefficients were derived from Henry’s law constants and used to assess the tendencies of NO2 toward fleeing the aqueous environments and concentrating in biological hydrophobic media. It is concluded, based only on the estimated aqueous medium-to-cell membrane partition coefficient for NO2, that such tendencies will be relatively small, and that they may account for an acceleration of chemical reactions in biological hydrophobic media with reaction kinetics that are first order on NO2 by a factor of approximately 3 ± 1. Thus, kinetic effects due to mass action will be relatively small but it is also important to recognize that because NO2 will tend to dissolve in cell membranes, reactions with cell membrane components will not be hindered by lack of physical solubility at these loci. In comparison to other gases, nitrogen dioxide is less hydrophobic than NO, O2 and N2.
PMCID: PMC2795573  PMID: 19540354
Nitrogen dioxide; partition coefficient; Henry’s law constant; solubility; kinetics; reactivity; compartmentation
5.  Desferrioxamine Inhibits Protein Tyrosine Nitration: Mechanisms and Implications 
Free radical biology & medicine  2012;53(4):951-961.
Tissues are exposed to exogenous and endogenous nitrogen dioxide (•NO2), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas phase •NO2 exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film. When RCM were exposed to •NO2 covered by +/− DFO: (i) DFO inhibited 3-NT formation more effectively than other HA and non-HA chelators; (ii) 3-NT inhibition occurred at very low [DFO] for prolonged times; and (iii) 3-NT formation was iron independent but inhibition required DFO present. DFO poorly reacted with •NO2 compared to ascorbate, assessed via •NO2 reactive absorption and aqueous phase oxidation rates, yet limited 3-NT formation at far lower concentrations. DFO also inhibited nitration under aqueous bulk phase conditions, and inhibited 3-NT generated by active myeloperoxidase “bound” to RCM. Per the above and kinetic analyses suggesting preferential DFO versus •NO2 reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents •NO2 addition, and thus nitration, and potentially influences biochemical functionalities.
PMCID: PMC3462664  PMID: 22705369
Desferrioxamine; nitrogen dioxide; membrane proteins; hydroxamic acids; epithelial lining fluid; nitration; tyrosine; tyrosyl radicals; repair; reduction
6.  Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation 
We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gas–induced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorine-exposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the post-exposure administration of ascorbate and deferoxamine.
PMCID: PMC3359900  PMID: 22162906
epithelial injury; epithelial repair; mucosubstances; ascorbate; deferoxamine; aerosol
7.  Ascorbate and Deferoxamine Administration after Chlorine Exposure Decrease Mortality and Lung Injury in Mice 
Chlorine (Cl2) gas exposure poses an environmental and occupational hazard that frequently results in acute lung injury. There is no effective treatment. We assessed the efficacy of antioxidants, administered after exposure, in decreasing mortality and lung injury in C57BL/6 mice exposed to 600 ppm of Cl2 for 45 minutes and returned to room air. Ascorbate and deferoxamine were administered intramuscularly every 12 hours and by nose-only inhalation every 24 hours for 3 days starting after 1 hour after exposure. Control mice were exposed to Cl2 and treated with vehicle (saline or water). Mortality was reduced fourfold in the treatment group compared with the control group (22 versus 78%; P = 0.007). Surviving animals in the treatment group had significantly lower protein concentrations, cell counts, and epithelial cells in their bronchoalveolar lavage (BAL). Lung tissue ascorbate correlated inversely with BAL protein as well as with the number of neutrophils and epithelial cells. In addition, lipid peroxidation was reduced threefold in the BAL of mice treated with ascorbate and deferoxamine when compared with the control group. Administration of ascorbate and deferoxamine reduces mortality and decreases lung injury through reduction of alveolar–capillary permeability, inflammation, and epithelial sloughing and lipid peroxidation.
PMCID: PMC3175564  PMID: 21131440
acute lung injury; oxidative stress; survival; aerosols; antioxidants
8.  Chlorine Gas Exposure Causes Systemic Endothelial Dysfunction by Inhibiting Endothelial Nitric Oxide Synthase–Dependent Signaling 
Chlorine gas (Cl2) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl2 exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl2 promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl2 for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl2 dose (0–400 ppm) and time after exposure (0–48 h) were determined. Exposure to Cl2 (250–400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (∼ 60%) in aorta isolated from Cl2–exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl2 exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl2–exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl2 exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms.
PMCID: PMC3175567  PMID: 21131444
endothelium; nitric oxide; inflammation; inhaled reactive oxidants
9.  Exposing Animals to Oxidant Gases 
Inhalation experiments using laboratory animals are performed under controlled conditions to assess the toxicity of and to investigate interventional strategies to ameliorate injury resulting from oxidant gas exposures. A variety of dynamic inhalation exposure systems that use whole-body or nose-only exposure chambers have been developed for rodents. In a whole-body exposure chamber, the animals are immersed in the test atmosphere, whereas in nose-only or head-only exposure systems, exposures are localized primarily to the head and/or nasal regions. There are advantages and disadvantages with both types of exposure approaches. Considerations such as animal number, exposure duration, end points of study, and availability of test material should influence the selection of a particular exposure system.
PMCID: PMC3136962  PMID: 20601630
chlorine; inhalation exposure; exposure chamber
10.  Mechanisms and Modification of Chlorine-induced Lung Injury in Animals 
Chlorine (Cl2) is a reactive oxidant gas used extensively in industrial processes. Exposure of both humans and animals to high concentrations of Cl2 results in acute lung injury, which may resolve spontaneously or progress to acute respiratory failure. Injury to airway and alveolar epithelium may result from chemical reactions of Cl2, from HOCl (the hydrolysis product of Cl2), and/or from the various reaction products, such as chloramines, that are formed from the reactions of these chlorinating species with biological molecules. Subsequent reactions may initiate self-propagating reactions and induce the production of inflammatory mediators compounding injury to pulmonary surfactant, ion channels, and components of lung epithelial and airway cells. Low-molecular-weight antioxidants, such as ascorbate, glutathione, and urate, present in the lung epithelial lining fluid and tissue, remove Cl2 and HOCl and thus decrease injury to critical target biological targets. However, levels of lung antioxidants of animals exposed to Cl2 in concentrations likely to be encountered in the vicinity of industrial accidents decrease rapidly and irreversibly. Our measurements show that prophylactic administration of a mixture containing ascorbate and desferal N-acetyl-cysteine, a precursor of reduced glutathione, prevents Cl2-induced injury to the alveolar epithelium of rats exposed to Cl2. The clinical challenge is to deliver sufficient quantities of antioxidants noninvasively, after Cl2 exposure, to decrease morbidity and mortality.
PMCID: PMC3136964  PMID: 20601632
ascorbate; N-acetyl-cysteine; chlorine; alveolar epithelium; hypochlorous acid

Results 1-10 (10)