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Published on: July 6, 2019
Inhibition of SHP2 by the Small Molecule Drug SHP099 Prevents Lipopolysaccharide-Induced Acute Lung Injury in Mice
Shuhui Ye1,2, Bowen Zuo1,3, Lenan Xu1,2
1Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, Zhejiang, China.
Abstract:
Excessive pulmonary inflammation in acute lung injury (ALI) causes high patient mortality. Anti-inflammatory therapy, combined with infection resistance, can help to prevent ALI and save lives. The expression of Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2) was found to be significantly higher in macrophages and lung tissues with ALI, and SHP2-associated MAPK pathways were activated by lipopolysaccharide (LPS). The knockdown of the SHP2 gene suppressed the LPS-induced release of inflammatory factors and the phosphorylation of regulators in the NF-κB pathways in macrophages. Our findings showed crosstalk between the LPS-induced inflammatory pathway and the SHP2-associated MAPK pathways. SHP2 inhibition could be a valuable therapeutic approach for inhibiting excessive inflammation in ALI. We discovered that giving SHP099, a specific allosteric inhibitor of SHP2, to mice with ALI and sepsis relieves ALI and significantly increases animal survival. Our study highlights the important role of SHP2 in ALI development and demonstrates the potential application of SHP099 for treating ALI.
Insights
Targeting SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase 2) can reduce pulmonary inflammation in acute lung injury (ALI). SHP2 inhibition with SHP099 shows therapeutic potential for ALI and sepsis, improving survival rates.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Acute lung injury (ALI) leads to excessive pulmonary inflammation and high mortality.
- The protein tyrosine phosphatase SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase 2) is implicated in inflammatory responses.
Purpose of the Study:
- To investigate the role of SHP2 in lipopolysaccharide (LPS)-induced inflammation in ALI.
- To evaluate the therapeutic potential of SHP2 inhibition for ALI treatment.
Main Methods:
- Assessed SHP2 expression in ALI models.
- Utilized gene knockdown to study SHP2 function in macrophages stimulated with LPS.
- Administered SHP099, an allosteric SHP2 inhibitor, to mice with ALI and sepsis.
Main Results:
- SHP2 expression was elevated in ALI lung tissues and macrophages.
- LPS activated SHP2-associated MAPK pathways and induced inflammatory factors.
- SHP2 knockdown suppressed LPS-induced inflammation and NF-κB pathway activation.
- SHP099 treatment alleviated ALI symptoms and improved survival in mice.
Conclusions:
- SHP2 plays a critical role in mediating LPS-induced inflammation in ALI.
- There is crosstalk between LPS-induced inflammatory pathways and SHP2-associated MAPK pathways.
- SHP2 inhibition, specifically with SHP099, represents a promising therapeutic strategy for ALI.
