Distinct roles of PI3Kδ and PI3Kγ in a toluene diisocyanate-induced
steroid insensitive murine asthma model
Abstract
Background: TDI-induced asthma is characterized by neutrophil-dominated
airway inflammation and often associated with poor responsiveness to
steroid treatment. Both PI3Kδ and PI3Kγ have been demonstrated to play
important proinflammatory roles in ovalbumin-induced asthma. We’ve
already reported that blocking pan PI3K effectively attenuated
TDI-induced allergic airway inflammation. Yet the specific functions of
PI3Kδ and PI3Kγ in TDI-induced asthma are still unclear. Methods: Male
BALB/c mice were first dermally sensitized and then challenged with TDI
to generate an asthma model. Sellective inhibitors of PI3Kδ (IC-87114,
AMG319) and PI3Kγ (AS252424, AS605240) as well as prednisone were
respectively given to the mice after each airway challenge. Results:
Treatment with IC-87114 or AMG319 after TDI exposure led to
significantly decreased airway hyperresponsiveness (AHR), less
neutrophil and eosinophil accumulation, attenuated airway smooth muscle
(ASM) thickening, less M1 and M2 macrophages in lung, as well as lower
levels of IL-4, IL-5, IL-6 and IL-18 in bronchoalveolar lavage fluid
(BALF) and recovered IL-10 production. While mice treated with AS252424
or AS605240 had increased AHR, more severe ASM thickening, larger
numbers of neutrophils and eosinophils, more M1 but less M2 macrophages,
and higher BALF levels of IL-4, IL-5, IL-6, IL-10, IL-12, IL-18 when
compared with those treated with vehicle. Conclusion: These data
revealed that pharmacological inhibition of PI3Kδ attenuates TDI-induced
steroid insensitive airway inflammation while PI3Kγ inhibition
exacerbates TDI-induced asthma, indicating distinct biological functions
of PI3Kδ and PI3Kγ in TDI-induced asthma.