Effects of Experimental Asthma on Inflammation and Lung Mechanics in Sickle Cell Mice

Abstract

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.

House Dust Mite-Induced Allergic Lung Inflammation Is Not Exacerbated in Sickle Cell Disease Mice

“…Similar severe histopathologic findings have been found in the mouse model of SCD, in which mice have allergic airway disease (AAD; essentially murine asthma) induced using the model allergen ovalbumin (OVA) [9, 10]. These mice also exhibit greater airway hyperreactivity (increased airway resistance after methacholine challenge) than WT mice with AAD, as measured by plethysmography [11]. Other consistent findings between humans and mice with SCD and asthma include high levels of allergen-induced immunoglobulin E (IgE) and Th2 cytokines in both the blood and respiratory mucosa [10-15].…”

“…Indeed, several reports [9, 10, 11, 15] by different groups have shown increased mortality, lung histopathology, and eosinophilia in SCD mice when compared to WT mice in the OVA model. Neither a high nor a low dose of HDM resulted in a difference between the genotypes in terms of these inflammatory outcomes.…”

“…Additionally, we found no difference between WT and SCD mice acutely exposed to a high dose of HDM in terms of serum cytokine concentrations. BALF cytokines in SCD mice with OVA-induced AAD have higher IL-5 [11], which is responsible for eosinophil chemotaxis and function. The lack of difference of IL-5 secretion in our study is supported by data from the study of Eiymo Mwa Mpollo et al [32], which also showed a lack of difference in IL-5 levelsbetween (chimeric) SCD and WT mice when exposed to HDM.…”

Wheezing in children with sickle cell disease

“…Taken together these data suggest that even under normal conditions, the lungs of SCD mice experience varying degrees of injury that may contribute to alterations in pulmonary physiology. 17 …”

The sickle cell mouse lung: proinflammatory and primed for allergic inflammation

“…Investigations of experimental asthma in the SCD mouse model to date reveal histopathologic evidence of an enhanced asthma phenotype, increased total plasma IgE, and elevated bronchoalveolar lavage fluid pro-inflammatory cytokines including IL-13 and IL-5 11 .…”