Inhibition of SHP2 by the Small Molecule Drug SHP099 Prevents Lipopolysaccharide-Induced Acute Lung Injury in Mice

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.