(A) In WT mice, SHP1 inhibits downstream neutrophil activation pathways initiated by SYK phosphorylation during acute lung injury caused by sterile agents (e.g., LPS), bacteria (e.g., P. aeruginosa), or viruses (e.g., SARS-CoV-2). As a result, the host effectively clears invading pathogens and/or resolves inflammation without causing substantial tissue damage. (B) However, acute lung injury in the absence of neutrophil Shp1 results in phosphorylated SYK that triggers excessive inflammatory cytokine production, degranulation, ROS release, and the formation of PAD-4–independent NETs, leading to perivascular inflammation and diffuse alveolar bleeding. SHP1 disruption–induced neutrophil hyperactivation also promotes the formation of large intravascular neutrophil clusters, leading to partial obstruction of the pulmonary arterioles, which, in turn, reduces neutrophil recruitment efficiency to infected alveolar spaces, thereby compromising their ability to eliminate bacteria. Together, these dysregulated neutrophil-driven events culminate in hemorrhagic and fatal acute lung injury.