While through efforts of ARDSnet and others, supportive therapies have improved survival;it remains that in the face of the many failed anti-pro-inflammatory mediator trials, from a medicinal/ molecular therapeutic perspective, the morbid condition of indirect/extra-pulmonary acute lung injury (iALI)(&it's more severe form;acute respiratory distress syndrome [ARDS]) have remained enigmatic. Thus, the need persists to clarify the pathological processes by which such insult(s) cause iALI, using salient models that more closely approximate the clinical scenario encountered in the critically injured/shocked and/or septic patient. In this respect, utilizing our dual insult model of iALI, resulting from hemorrhagic shock (Hem;a 'priming'insult) followed by polymicrobial septic challenge (CLP;'triggering'event) (stimuli which [as produced here] do not induce ALI alone), we have recently uncovered a novel role for a cell surface co-inhibitory receptor molecule, known as Programmed cell death receptor (PD)-1, in the developing pathology of iALI. Using PD-1 -/- mice in this model of iALI, we have made some initial observations that point to the proximal significance of this family of molecules: 1) following Hem alone as well as Hem/CLP, there are significant changes in blood/ pulmonary phagocyte, lymphocyte, as well as lung endothelial and epithelial cell expression of PD-1 and/or it's ligand PD- L1;2) PD-1 gene deficiency suppresses indices of lung cell apoptosis (Ao), reduces aspects of lung tissue inflammation and markers of neutrophil (PMN) activation;3) PD-1 -/- mice have a marked survival advantage over the wild-type control mice subjected to Hem/CLP;and 4) higher %PD-1+ blood leukocytes were detected in ICU patients with ALI that eventually succumbed vs. survivors. With this in mind, we propose the following hypothesis: that the classic co-inhibitory receptor, PD-1 and/or its ligands (PD-L1 or PD-L2), play a novel role(s) in regulating the development of iALI via induction of local pulmonary cell Ao and/or local tissue inflammation. The 2 Aims below test this hypothesis:
AIM 1 : Since neither Hem nor CLP alone are sufficient to produce marked indices of iALI, we will determine the degree to which the expression of PD-1, as well as its ligands, on lung cells is altered in response to Hem alone vs. the combined insult of Hem/ CLP (which produces fulminate iALI). Subsequently, we will establish the pathological role of not only PD-1, but also its ligands in the development of iALI. Finally, we will determine the extent to which these changes also occur in SICU/TICU patients.
AIM 2 : By utilizing selective cell depletion, chimeric construction, and/or cell lineage add-back, we will establish the extent to which the expression of PD-1 or PD-L1 or PD-L2 on a given effecter cell and/or target cell population is critical to the development of iALI. Concomitantly, we will begin to elucidate what the ligation of PD-1 and/or PD-L does to various leukocyte and/or endothelial/ epithelial cell functions and what mechanisms control the expression of these co-inhibitor/ ligands.
Acute lung injury is reported to be the most common form of organ dysfunction encountered in critically ill patients in trauma/ surgical/ medical intensive car units. This study is designed to determine what the contribution of family of co-inhibitory cell surface-associated molecules, expressed on immune (i.e., neutrophil, macrophage, dendritic cell, etc.) and non-immune cell's (i.e., epithelial and endothelial cell), in the develop of acute lung injury in the critically ill surgical/trauma patient. The role of co-inhibitory molecule geneswill be established using genetically altered mice as well as drug interventions directed at these molecules in the dual insult experimental model of shock (due to blood loss) followed by septic challenge in mice, along with observational patient based studies. It is our firm belief that the results of these studies will provide information that not only should allow us to better understand the pathobiology of acute lung injury but also its attenuation.
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