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This article is available online at http://www.jlr.org plays important roles in limiting pulmonary infl ammation and oxidative stress, which if not prevented, will decrease pulmonary artery vasodilatation and increase airway hyperresponsiveness. Although apolipoprotein A-I (apoA-I), the major antiatherogenic apolipoprotein of HDL, is well recognized for protecting the heart against vascular disease, it also protects other vascular beds and organs. Recent studies provide new evidence supporting the notion that HDL plays a protective role in the lung. ABCA1, which interacts with lipid-poor apoA-I, was earlier shown to be essential for maintaining normal lipid composition and architecture of the lung as well as respiratory physiology ( 1 ). More recently, proteomic studies revealed that homozygous Abstract The relationship between high-density lipoprotein and pulmonary function is unclear. To determine mechanistic relationships we investigated the effects of genetic deletion of apolipoprotein A-I (apoA-I) on plasma lipids, paraoxonase (PON1), pro-infl ammatory HDL (p-HDL), vasodilatation, airway hyperresponsiveness and pulmonary oxidative stress, and infl ammation. ApoA-I null ( apoA-IϪ / Ϫ ) mice had reduced total and HDL cholesterol but increased pro-infl ammatory HDL compared with C57BL/6J mice. Although PON1 protein was increased in apoA-I Ϫ / Ϫ mice, PON1 activity was decreased. ApoA-I defi ciency did not alter vasodilatation of facialis arteries, but it did alter relaxation responses of pulmonary arteries. Central airway resistance was unaltered. However, airway resistance mediated by tissue dampening and elastance were increased in apoA-I Ϫ / Ϫ mice, a fi nding also confi rmed by positive endexpiratory pressure (PEEP) studies. Infl ammatory cells, collagen deposition, 3-nitrotyrosine, and 4-hydroxy-2-nonenal were increased in apoA-I Ϫ / Ϫ lungs but not oxidized phospholipids. Colocalization of 4-hydroxy-2-nonenal with transforming growth factor ␤ -1 (TGF ␤ -1 was increased in apoA-I Ϫ / Ϫ lungs. Xanthine oxidase, myeloperoxidase and endothelial nitric oxide synthase were increased in apoA-I Ϫ / Ϫ lungs. Dichlorodihydrofl uorescein-detectable oxidants were increased in bronchoalveolar lavage fl uid (BALF) in apoA-I Ϫ / Ϫ mice. In contrast, BALF nitrite+nitrate levels were decreased in apoA-I Ϫ / Ϫ mice. These data demonstrate that apoA-I

Asthma is a comorbid condition associated with increased rates of pain, acute chest syndrome, and premature death in human sickle cell disease (SCD). We developed an experimental asthma model in SCD and control mice expressing either normal human or murine hemoglobin to determine its effect on mortality and lung pathology. To induce lung inflammation, experimental mice were sensitized to ovalbumin (OVA) by subcutaneous OVA implantation (Sen), allowed 2 weeks to recover, and then divided into 2 groups, each receiving over a subsequent 10-day period the same dosage of aerosolized OVA but 2 different levels of exposure: 15 minutes (LoSen) and 30 minutes (HiSen). During recovery, 10% of SCD mice died compared with no deaths in control mice. An additional 30% of HiSen SCD mice died during aerosolization compared with 10% in LoSen SCD. Histologic indices of lung inflammation (eg, eosinophil recruitment, airway and vessel wall thickening, and immunoreactive TGF␤ and fsp-1) and bronchial alveolar lavage fluid eosinophil peroxidase activity differentially increased in sensitized mice compared with unsensitized mice. Our findings indicate SCD mice with experimentally induced asthma are more susceptible to death and pulmonary inflammation compared with control mice, suggesting that asthma contributes significantly to morbidity and mortality in SCD. (Blood. 2008;112:2529-2538) IntroductionThe major causes of morbidity and mortality in sickle cell disease (SCD) are initiated by tissue ischemia and infarction due to vascular occlusion that results in progressive organ damage. The etiology of vaso-occlusion is unclear and likely reflects the complex interplay between the sickle red blood cell, the injured vessel wall, and increased inflammation. In support of this notion, there is considerable evidence for increased inflammation in both human and murine SCD. The leukocyte count is elevated in SCD and correlates with a more severe clinical course, including increased risk of stroke and early death. [1][2][3][4] In addition, patients with SCD have chronically elevated acutephase proteins, which often increase further during crisis. 5 The fact that patients with SCD have increased numbers of circulating endothelial cells that increase to even higher levels during times of vaso-occlusive crises, provide strong evidence that endothelial inflammation and injury play important roles in the mechanisms impairing vascular function in SCD. 6 These circulating endothelial cells express an activated phenotype, including increased expression of the adhesive molecules VCAM-1, E-selectin, and ICAM-1. 6 In parallel with these human studies, additional experiments showed that sickle cell disease mice also have increased circulating endothelial cells that express higher levels of E-selectin, VCAM, and ICAM-1. 7 Other studies have shown that sickle cell disease increases the expression of tissue factor in the veins of the lungs in response to ischemia/ reperfusion by a mechanism that can be inhibited by lovastatin. 8 Moreover, plasma levels of th...

Experimental asthma increases eosinophil and collagen deposition in the lungs of sickle cell disease (SCD) mice to a greater extent than in control mice. However, the effects of asthma on inflammation and airway physiology remain unclear. To determine effects of asthma on pulmonary inflammation and airway mechanics in SCD mice, hematopoietic stem cell transplantation was used to generate chimeric SCD and hemoglobin A mice. Experimental asthma was induced by sensitizing mice with ovalbumin (OVA). Airway mechanics were assessed using forced oscillation techniques. Mouse lungs were examined histologically and physiologically. Cytokine, chemokine, and growth factors in bronchoalveolar lavage fluid were determined by multiplex. IgE was quantified by ELISA. LDH was quantified using a colorimetric enzymatic assay. At baseline (nonsensitized), chimeric SCD mice developed hemolytic anemia with sickled red blood cells, mild leukocytosis, and increased vascular endothelial growth factor and IL-13 compared with chimeric hemoglobin A mice. Experimental asthma increased perialveolar eosinophils, plasma IgE, and bronchoalveolar lavage fluid IL-1b, IL-4, IL-6, and monocyte chemotactic protein 1 in chimeric hemoglobin A and SCD mice. IFN-g levels were reduced in both groups. IL-5 was preferentially increased in chimeric SCD mice but not in hemoglobin A mice. Positive end-expiratory pressures and methacholine studies revealed that chimeric SCD mice had greater resistance in large and small airways compared with hemoglobin A mice at baseline and after OVA sensitization. SCD alone induces a baseline lung pathology that increases large and small airway resistance and primes the lungs to increased inflammation and airway hyperresponsiveness after OVA sensitization.