Asthma affects millions of people worldwide and is one of the most common inflammatory airway diseases.
Asthma phenotypes are quite complex and categorized as eosinophilic, mixed granulocytic (presence of both eosinophils and neutrophils in the airways) and neutrophilic. Mixed granulocytic
asthma requires large doses of inhaled
corticosteroids, which are often insufficient in controlling airway
inflammation. Therefore, there is a medical need to test newer
therapies to control granulocytic
inflammation. Lymphocyte specific
protein tyrosine kinase (LCK) signaling has gained momentum in recent years as a molecular target in inflammatory diseases such as
asthma. LCK is expressed in lymphocytes and is required for inflammatory intracellular signaling in response to antigenic stimulation. Therefore, efficacy of LCK inhibitor,
A770041 was tested in cockroach (CE)-induced
corticosteroid insensitive murine model of
asthma. The effect of LCK inhibitor was investigated on granulocytic airway
inflammation, mucus production, p-LCK and downstream signaling molecules such as p-PLCĪ³, GATA3, p-STAT3 in CD4+ T cells. Moreover, its effects were also studied on Th2/Th17 related
cytokines and oxidative stress parameters (iNOS/
nitrotyrosine) in neutrophils/macrophages. Our study shows that CE-induced p-LCK levels are concomitant with increased neutrophilic/eosinophilic
inflammation and mucus hypersecretion which are significantly mitigated by
A770041 treatment.
A770041 also caused marked attenuation of CE-induced pulmonary levels of
IL-17A levels but not completely. However,
A770041 in combination with
dexamethasone caused complete downregulation of mixed granulocytic airway
inflammation as well as Th2/Th17 related immune responses. These results suggest that combination of LCK inhibition along with
corticosteroids may be pursued as an alternative strategy to completely treat mixed granulocytic
asthma.