Acute lung injury (ALI), a common and often lethal illness, is characterized by widespread and injurious inflammation. Many features of ALI, including its pathophysiology and therapeutic interventions remain incompletely defined, in part because the cellular and molecular mechanisms are poorly understood. Although the role of leukocytes in ALI has been well studied, investigations into platelet function in ALI have been relatively infrequent and there are many gaps in our knowledge. Recent evidence from our group and others suggests that platelets have important functions that contribute to the development and progression of ALI. Platelets are known to possess a transcriptome of messenger RNAs (mRNAs) that they receive from megakaryocytes. Unexpectedly, we recently demonstrated that megakaryocytes also transfer intron- containing pre-mRNAs to platelets. In response to activating signals, anucleate platelets splice these pre-mRNAs and reassembled them into mature mRNA transcripts which are translated into functional proteins. Two of the spliced mRNAs we have characterized code for interleukin-1? (IL-1?), an inflammatory cytokine, and tissue factor (TF), a regulator of coagulation. Both synthesized proteins have functional activity central to the pathobiology of ALI. In our preliminary data from sepsis patients (a risk factor for ALI), we demonstrated that the incidence of TF pre-mRNA splicing in platelets is markedly increased and predicts greater illness severity and higher mortality risk. These pilot data suggest a role for platelet-derived pre-mRNA splicing events in ALI. We now propose integrated clinical and basic science studies to explore these observations. A central hypothesis is that pre-mRNA splicing events in platelets are dysregulated in ALI, and that the expression of spliced messages in platelets provides predictive information in addition to contributing to pathologic sequellae. Two integrated specific aims will examine splicing patterns in (1) patients with ALI and (2) patients at-risk for ALI. These studies will generate new insights into the molecular pathobiology of ALI and may provide new targets for therapeutic interventions. Acute lung injury is a common disorder that results when the body's responses to infection become uncontrolled. Acute lung injury has high mortality and is a major public health issue. The studies proposed in this application explore newly-identified cellular and molecular mechanisms using samples from patients with this disorder and may yield new ways to chart the course of acute lung injury in individual patients, and have the potential to identify new molecular targets for therapeutic intervention.
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