Airway inflammation in sickle cell disease—A translational perspective

Abstract

Asthma and sickle cell disease (SCD) are common chronic conditions in children of African ancestry that are characterized by cough, wheeze, and obstructive patterns on pulmonary function. Pulmonary function testing in children with SCD has estimated a prevalence of obstructive lung disease ranging from 13% to 57%, and airway hyper-responsiveness of up to 77%, independent of a diagnosis of asthma. Asthma co-existing with SCD is associated with increased risk of acute chest syndrome (ACS), respiratory symptoms, pain episodes, and death. However, there are inherent differences in the pathophysiology of SCD and asthma. While classic allergic asthma in the general population is associated with a T-helper 2 cell (Th-2 cells) pattern of cell inflammation, increased IgE levels and often positive allergy testing, inflammation in SCD is associated with different inflammatory pathways, involving neutrophilic and monocytic pathways, which have been explored to a limited extent in mouse models and with a dearth of human studies. The current review summarizes the existent literature on sickle cell related airway inflammation and its cross roads with allergic asthma-related inflammation, and discusses the importance of further elucidating and understanding these common and divergent inflammatory pathways in human studies to facilitate development of targeted therapy for children with SCD and pulmonary morbidity.

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

“…Additionally, De et al [35] recently reviewed the literature in terms of the differences and similarities between human and murine studies of comorbid asthma in SCD. Based on their interpretation of a human study by An et al [13] (which showed that there was an increased prevalence of high total IgE titers than diagnosis of asthma in children with SCD), De et al [35] postulate that the very high titers of IgE that are induced in SCD mice after OVA sensitization are the result of enhanced inflammatory reactions to stimuli, and not necessarily other drivers of AAD. Our lack of high IgE titers and the normal levels of lung inflammation in SCD mice after exposure to HDM support this hypothesis.…”

Asthma and the outcome of sickle cell disease

“…One proposed mechanism for increased airway inflammation in SCD children is that haemolysis contributes to airway changes similar to those found in asthma. Haemolysis causes hydrolysis of membrane phospholipids into arachidonic acid, which leads to formation of leukotriene B4 which is also associated with eosinophilic asthma [70]. Elevated leukotriene levels have been found in SCD in both murine and human studies [70].…”

“…Haemolysis causes hydrolysis of membrane phospholipids into arachidonic acid, which leads to formation of leukotriene B4 which is also associated with eosinophilic asthma [70]. Elevated leukotriene levels have been found in SCD in both murine and human studies [70]. Placenta growth factor, which is elevated in SCD has been shown in a mouse study to exacerbate airway hyperresponsiveness and may link the leukotriene and Th2-mediated pathways in asthma [71].…”

“…Secondly, lysed erythrocytes release arginase, reducing the availability of arginine for synthesis of nitric oxide. This causes vasoconstriction, endothelial activation and proliferation [ 70,72].…”

A physicians survey assessing management of pulmonary airway involvement in sickle cell disease

“…While many studies have associated the presence of LAO and/ or AHR with the diagnosis of asthma in SCD, there is an increasing awareness that the pathophysiology of airway involvement in SCD may be different from classic allergic asthma, and may represent airway inflammation secondary to lung injury from vaso‐occlusive episodes or hemolysis in SCD . Further, allergic asthma may also be an independent comorbid condition in SCD in conjunction with an atopic predisposition.…”