Histopathology of experimentally induced asthma in a murine model of sickle cell disease

Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Blood Research Institute, Children's Research Institute, Cardiovascular Center, Milwaukee, WI 53226, USA.
Blood (Impact Factor: 10.45). 07/2008; 112(6):2529-38. DOI: 10.1182/blood-2008-01-132506
Source: PubMed


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 TGFbeta 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.

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Available from: Dorothee Weihrauch, Mar 11, 2014
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    • "This inflammation could in turn result in a propensity towards clinical asthma. Supporting this hypothesis is the documentation of increased mortality and an enhanced inflammatory response to allergens in mice with SCD and experimentally induced asthma [37]. Leukotrienes are a particularly intriguing commonality between asthma and SCD. "
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    ABSTRACT: Asthma is a common comorbid factor in sickle cell disease (SCD). However, the incidence of asthma in SCD is much higher than expected compared to rates in the general population. Whether "asthma" in SCD is purely related to genetic and environmental factors or rather is the consequence of the underlying hemolytic and inflammatory state is a topic of recent debate. Regardless of the etiology, hypoxemia induced by bronchoconstriction and inflammation associated with asthma exacerbations will contribute to a cycle of sickling and subsequent complications of SCD. Recent studies confirm that asthma predisposes to complications of SCD such as pain crises, acute chest syndrome, and stroke and is associated with increased mortality. Early recognition and aggressive standard of care management of asthma may prevent serious pulmonary complications and reduce mortality. However, data regarding the management of asthma in SCD is very limited. Clinical trials are needed to evaluate the effectiveness of current asthma therapy in patients with SCD and coincident asthma, while mechanistic studies are needed to delineate the underlying pathophysiology.
    11/2013; 2013(17):604140. DOI:10.1155/2013/604140
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    ABSTRACT: Secondary pulmonary hypertension (PH) is a leading cause of mortality and morbidity in patients with hemolytic anemias, including sickle cell disease (SCD) and thalassemia. Asthma is another common co-morbidity in SCD that has been linked to early death. The high frequency of asthma in this population cannot be attributed to genetic predisposition alone, and likely reflects in part, the contribution of overlapping mechanisms shared between these otherwise distinct disorders. There is accumulating evidence that dysregulated arginine metabolism and elevated arginase activity contributes to a number of pulmonary conditions. Patients with hemolytic disorders are at risk for lung complications triggered or worsened by hemolysis-driven release of erythrocyte arginase and low nitric oxide (NO) bioavailability. Inactivation of NO correlates with hemolytic rate and is associated with the erythrocyte release of cell-free hemoglobin, which consumes NO directly, and the simultaneous release of the arginine-metabolizing enzyme arginase, which limits bioavailability of the NO synthase substrate arginine during the process of intravascular hemolysis. Rapid consumption of NO is accelerated further by oxygen radicals in a milieu of oxidative stress common to hemolytic disorders. Once released into circulation, arginase will convert arginine to ornithine, which in turn is the precursor to proline, an amino acid involved in collagen formation, lung fibrosis, airway remodeling and vascular smooth muscle proliferation, common features of pulmonary dysfunction in thalassemia and SCD. Evidence supporting the role of arginase in sickle cell lung disease will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered. The hemoglobinopathies are among the most common genetic disorders in the world. An estimated 5% of the global population are carriers of variants in either or globin genes resulting in two major red blood cell disorders, the thalassemia syndromes and sickle cell disease (SCD). These are autosomal recessive conditions that affect over 30 million people worldwide [1-5]. SCD occurs in individuals of African, Caribbean, Mediterranean, Arab and other Middle Eastern descent, and affects more than 70,000 people in the US. Although an accurate account of the global burden of SCD is unknown, recent newborn screening analysis for hemoglobinopathies in the state of California revealed an incidence of 1/393 African American infants born with SCD over an 8.5 year time period [6]. whereas in sub-Saharan Africa, it is estimated that 1-4% of the population is born with this disease [4]. Of interest, 12.5% of sickle-beta thalassemia infants born in California were of Hispanic origin [6].
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