Asthma is a co-morbid condition that increases morbidity and mortality of children who have sickle cell disease (SCD). Recently, we reported that experimental asthma induced by ovalbumin (OVA) sensitization of SCD mice increases pulmonary inflammation and collagen deposition in SCD mice to a much greater extent than in OVA-sensitized control mice. Preliminary Results show that OVA-sensitization also increases airway resistance in SCD mice to a greater degree than in OVA-sensitized controls. Additionally, OVA-sensitization increases proinflammatory high-density lipoprotein (HDL) levels in SCD mice, indicating that HDL from SCD+asthma mice is oxidatively modified to a greater extent than HDL from SCD mice. Further proof that HDL plays an important role in preventing pulmonary inflammation comes from histology and airway response studies in mice lacking apolipoprotein A-I (apoA-I), the major anti- inflammatory apolipoprotein in HDL. Genetic loss of HDL via apoA-I deletion dramatically increases pulmonary inflammation and collagen deposition and increases airway resistance even without OVA sensitization. On the basis of these findings, we hypothesize that the oxidative stress induced by asthma and SCD synergize to increase HDL oxidation, which then impairs HDL function. Further, we hypothesize that the loss of HDL function (either directly or indirectly) increases endothelial cell activation (increased VCAM-1 expression) in pulmonary vessels, which in turn, increases the susceptibility of SCD+asthma mice to pulmonary vaso-occlusion when subjected to hypoxia/reperfusion (H/R) injury. To test these hypotheses we propose 3 aims.
Aim 1 will determine if the combination of asthma and SCD increases oxidation of HDL and therefore HDL function and if targeting oxidative stress induced by 1) xanthine oxidase (XO);2) myeloperoxidase (MPO);3) cell free hemoglobin (Hb);and, 4) oxidized lipids prevents oxidation of HDL and other lipoproteins in the SCD mice with asthma.
Aim 2 will determine if the combination of asthma plus SCD impairs pulmonary artery vasodilatation, increases pulmonary arterial hypertension (PAH) and increases airway hyperresponsiveness. These studies will reveal whether targeting oxidative stress (i.e., XO, MPO, free Hb and oxidized lipids) actually improves HDL function and restores pulmonary and airway function.
Aim 3 will determine the extent to which VCAM-1 (and ICAM-1) mediates red cell vascular congestion in SCD+asthma mice;whether targeting oxidative enzyme activity, free Hb or oxidized lipids attenuates pulmonary inflammation and reduces vaso-congestion;and finally, whether treatments with apoA-I can reduce pulmonary inflammation and vaso-congestion. If our hypotheses are correct, restoring HDL function should decrease pulmonary inflammation and attenuate vaso-occlusion in the lungs of SCD+asthma mice. Findings from our studies will reveal new insight into the inflammatory and oxidative mechanisms by which asthma increases airway hyperresponsiveness and PAH in SCD. Novel therapeutic strategies will be used to determine the extent to which asthma increases these four different oxidative pathways to induce pulmonary inflammation, airway hyperresponsiveness and vaso-occlusion in SCD.
Asthma increases morbidity and mortality in individuals afflicted with sickle cell disease. We want to determine why asthma increases inflammation and red cell vascular congestion in lungs of sickle cell mice. We think that the oxidative stress induced by asthma coupled with oxidative stress induced by sickle cell disease team up to oxidize high-density lipoprotein (HDL). Oxidation changes """"""""good cholesterol"""""""" into """"""""bad cholesterol,"""""""" which can no longer clean up blood vessels and airways. Thus, lung tissues bind more white blood cells causing the airways to shrink, which restricts airflow. This decreases blood and oxygen exchange in the lung, which in turn, increases red cell sickling and vaso-occlusion in sickle cell disease. We plan to reduce oxidative stress and decrease HDL oxidation by using a combination of standard and novel drug therapies. If we are correct, then our drug therapies should improve blood vessel function and decrease airway resistance in SCD mice with experimental asthma.
|Strzepa, Anna; Pritchard, Kirkwood A; Dittel, Bonnie N (2017) Myeloperoxidase: A new player in autoimmunity. Cell Immunol 317:1-8|
|Weihrauch, Dorothee; Krolikowski, John G; Jones, Deron W et al. (2017) Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice. J Vis Exp :|
|Yu, Guoliang; Liang, Ye; Huang, Ziming et al. (2016) Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke. J Neuroinflammation 13:119|
|Weihrauch, Dorothee; Krolikowski, John G; Jones, Deron W et al. (2016) An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice. PLoS One 11:e0151999|
|Wandersee, Nancy J; Maciaszek, Jamie L; Giger, Katie M et al. (2015) Dietary supplementation with docosahexanoic acid (DHA) increases red blood cell membrane flexibility in mice with sickle cell disease. Blood Cells Mol Dis 54:183-8|
|Ataga, Kenneth I; Hinderliter, Alan; Brittain, Julia E et al. (2015) Association of pro-inflammatory high-density lipoprotein cholesterol with clinical and laboratory variables in sickle cell disease. Hematology 20:289-96|
|Zhang, Hao; Ray, Avijit; Miller, Nichole M et al. (2015) Inhibition of Myeloperoxidase at the Peak of Experimental Autoimmune Encephalomyelitis Restores Blood-Brain-Barrier Integrity and Ameliorates Disease Severity. J Neurochem :|
|Yan, Xiaocai; Yan, Mingfei; Guo, Yihe et al. (2015) R-Ras Regulates Murine T Cell Migration and Intercellular Adhesion Molecule-1 Binding. PLoS One 10:e0145218|
|Xu, Hao; Wandersee, Nancy J; Guo, YiHe et al. (2014) Sickle cell disease increases high mobility group box 1: a novel mechanism of inflammation. Blood 124:3978-81|
|Rymaszewski, Amy L; Tate, Everett; Yimbesalu, Joannes P et al. (2014) The role of neutrophil myeloperoxidase in models of lung tumor development. Cancers (Basel) 6:1111-27|
Showing the most recent 10 out of 22 publications