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\begin{document}

\title{Spiro-isoxazolonechromans-3 alleviates LPS-induced acute lung injury in
mice via inhibiting inflammation through modulating JAK1/STAT pathway}



\author[1]{Yunhui Zhang}%
\author[1]{Baoping Xiong}%
\author[1]{Yue Li}%
\author[1]{Jing Zhou}%
\author[1]{Hongmei Qiu}%
\author[2]{Hailin Liu}%
\author[2]{Yingqing Nie}%
\author[1]{Zongjie Gan}%
\author[1]{Ping Deng}%
\author[2]{yingju liu}%
\affil[1]{Chongqing Medical University}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\begin{abstract}
Acute lung injury (ALI) is a serious clinical disease with a mortality
rate of 30-40\%. We designed and synthesized a structurally novel
compound, Spiro-isoxazolonechromans-3 (SI-3), to seek a new approach for
treating excessive inflammation in ALI. In the present study, we induced
RAW 264.7 cells with LPS and injected LPS intraperitoneally in BALB/c
mice to establish an ALI model. Molecular docking results showed SI-3
located in the hydrophobic pocket of Janus Kinase 1 (JAK1) and
interacted with JAK1 through amino acid residue Leu959. SI-3 selectively
inhibited the JAK1 enzyme activity with an IC50 of 9 nM and is
non-toxic. In vitro, LPS-induced macrophage proliferation, activation,
and secretion of inflammatory cytokines were inhibited by SI-3, which
promoted macrophage apoptosis. In vivo, SI-3 improved the survival rate
of ALI mice by reducing pathological lung injury and inflammatory
response. Both in vivo and in vitro, we discovered that SI-3 exerted a
downregulatory impact on the JAK1-STAT pathway according to the results
of western-blot studies and showed the same effect in
JAK1-overexpressing macrophages. Overall, SI-3 could reduce LPS-induced
inflammatory response and promote macrophage apoptosis by inhibiting
JAK1 kinase and affecting JAK1/JAK3-STAT pathway, resulting in
significant anti-inflammatory effects, which alleviated the LPS-induced
ALI in mice.%
\end{abstract}%



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