SCCOR in Translational Research in Acute Lung Injury

本SCCOR提案的总体目标是确定引发和维持急性肺损伤（AL 1）的病理生理机制。本申请的中心假设是在ALI/ARDS患者的肺中同时诱导促炎和抗炎细胞因子。这些因子中的细胞因子失衡触发ALI/ARDS的急性渗出期，并产生有利于受损的肺先天免疫应答和纤维增生性修复应答的肺泡环境。本SCCOR将采用实验室到床边的方法来检验以下项目假设： 1.趋化因子TARC及其受体CCR 4通过结构细胞和白细胞的表达通过调节早期细胞因子产生、toll样受体表达和白细胞活化/募集代表脓毒症应答的关键调节组分。 2. AL 1诱导CC趋化因子MCP-1的全身释放，其介导成纤维细胞祖细胞（纤维细胞）向肺泡的募集，导致纤维细胞成熟、胶原沉积和纤维增殖。 3. AL 1中肺泡巨噬细胞（AM）的活化状态受过氧化物酶体增殖物激活受体-γ（PPAR-gamma）调节，并且PPAR-gamma表达/活化的幅度可预测患有ALI/ARDS的患者的临床过程。 4.成纤维细胞祖细胞存在于患有AL 1的患者的肺泡中，并且这些细胞的表型受遗传和微环境因素两者控制。此外，肺泡间充质细胞的存在和/或表型可预测ALI/ARDS患者的急性和长期结局。 5. GM-CSF的应用将改善ALI/ARDS患者的临床结局。 我们的SCCOR代表了一个独特的多学科和多中心合作，该合作将具有ALl临床和基础研究专业知识的多样化研究者群体联合起来，并提供了对大量ARDS患者的访问，以确保成功完成拟议的研究。这些研究将为AL 1中肺部炎症和修复的调节提供重要的见解，这可能导致评估和治疗这种毁灭性疾病的新方法。

The overall objective of this SCCOR proposal is to identify pathophysiological mechanisms that initiate and perpetuate acute lung injury (ALl). The central hypothesis of this application is that concurrent induction of pro-inflammatory and anti-inflammatory cytokines occurs in the lungs of patients with ALI/ARDS. A cytokine imbalance in these factors triggers the acute exudative phase of ALI/ARDS and creates an alveolar milieu which favors impaired pulmonary innate immune responses and fibroproliferative repair responses. This SCCOR will utilize a bench-to-bedside approach to test the following project hypotheses: 1. The expression of the chemokine TARC and it's receptor CCR4 by structural cells and leukocytes represent key regulatory components of the septic response by modulating early cytokine production, toll-like receptor expression, and leukocyte activation/recruitment. 2. ALl induces the systemic release of the CC chemokine MCP-1, which mediates the recruitment of fibroblast progenitor cells (fibrocytes) to the alveolus, resulting in fibrocyte maturation, collagen deposition, and fibroproliferation. 3. The activation state of the alveolar macrophage (AM) in ALl is regulated by peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and the magnitude of PPAR-gamma expression/activation is predictive of the clinical course in patients with ALI/ARDS. 4. Fibroblast progenitor cells are present in the alveolus of patients with ALl, and the phenotype of these cells is controlled by both genetic and microenvironmental factors. Furthermore, the presence and/or phenotype of alveolar mesenchymal cells is predictive of acute and long-term outcomes in patients with ALI/ARDS. 5. The administration of GM-CSF will improve clinical outcomes in patients with ALI/ARDS. Our SCCOR represents a unique multidisciplinary and multicenter collaboration that unites a diverse group of investigators with expertise in the clinical and basic investigation of ALl, as well as provides access to a large population of ARDS patients to ensure successful completion of the proposed studies. These studies will provide important insights into the regulation of pulmonary inflammation and repair in ALl, which may lead to novel approaches in both the assessment and treatment of this devastating disease.