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\title{Distinct roles of PI3K\selectlanguage{greek}δ \selectlanguage{english}and PI3K\selectlanguage{greek}γ \selectlanguage{english}in a toluene diisocyanate-induced
steroid insensitive murine asthma model\selectlanguage{english}}



\author[1]{Caiyun Xu}%
\author[2]{Shuyu Chen}%
\author[3]{Yao Deng}%
\author[4]{Jiafu Song}%
\author[5]{Jiahui Li}%
\author[5]{Xin Chen}%
\author[5]{Ping Chang}%
\author[6]{Lihong Yao}%
\author[5]{Haixiong Tang}%
\affil[1]{Department of Critical Care Medicine, Lianyungang First People’s Hospital, Affiliated Hospital of Xuzhou Medical College}%
\affil[2]{Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, Second Clinical Medical College, Jinan University (Shenzhen People's Hospital)}%
\affil[3]{Guangzhou Medical University}%
\affil[4]{Department of Respiratory and Critical Care Medicine, Lianyungang First People’s Hospital, Affiliated Hospital of Xuzhou Medical College}%
\affil[5]{Southern Medical University}%
\affil[6]{ Guangzhou Medical University}%


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  \date{June 09, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: TDI-induced asthma is characterized by neutrophil-dominated
airway inflammation and often associated with poor responsiveness to
steroid treatment. Both PI3K\selectlanguage{greek}δ \selectlanguage{english}and PI3K\selectlanguage{greek}γ \selectlanguage{english}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
PI3K\selectlanguage{greek}δ \selectlanguage{english}and PI3K\selectlanguage{greek}γ \selectlanguage{english}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 PI3K\selectlanguage{greek}δ \selectlanguage{english}(IC-87114,
AMG319) and PI3K\selectlanguage{greek}γ \selectlanguage{english}(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 PI3K\selectlanguage{greek}δ \selectlanguage{english}attenuates TDI-induced
steroid insensitive airway inflammation while PI3K\selectlanguage{greek}γ \selectlanguage{english}inhibition
exacerbates TDI-induced asthma, indicating distinct biological functions
of PI3K\selectlanguage{greek}δ \selectlanguage{english}and PI3K\selectlanguage{greek}γ \selectlanguage{english}in TDI-induced asthma.%
\end{abstract}%



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