SCCOR in Translational Research in Acute Lung Injury

SCCOR建议的总体目标是确定引发和延续急性肺损伤(ALL)的病理生理机制。这一应用的中心假设是在ALI/ARDS患者的肺中同时诱导促炎和抗炎细胞因子。这些因素中的细胞因子失衡触发了ALI/ARDS的急性渗出期，并创造了有利于受损的肺固有免疫反应和纤维增殖性修复反应的肺泡环境。该SCCOR将使用工作台到床边的方法来测试以下项目假设： 1.结构细胞和白细胞表达趋化因子TARC及其受体CCR4，通过调节早期细胞因子的产生、Toll样受体的表达和白细胞的激活/募集，是脓毒症反应的关键调节成分。 2.ALL诱导全身释放CC趋化因子MCP-1，介导成纤维细胞前体细胞(成纤维细胞)募集到肺泡，导致成纤维细胞成熟、胶原沉积和纤维增殖。 3.ALL患者肺泡巨噬细胞(AM)的激活状态受PPAR-γ的调节，PPAR-γ的表达/激活程度可预测ALI/ARDS患者的临床病程。 4.ALL患者肺泡内存在成纤维细胞前体细胞，其表型受遗传因素和微环境因素的共同控制。此外，肺泡间充质细胞的存在和/或表型可预测ALI/ARDS患者的急性和长期预后。 5.应用GM-CSF可改善ALI/ARDS患者的临床预后。 我们的SCCOR代表着一种独特的多学科和多中心合作，将具有对所有人的临床和基础研究专业知识的不同研究人员团结在一起，并提供接触大量ARDS患者的机会，以确保成功完成拟议的研究。这些研究将为调节肺部炎症和修复提供重要的见解，这可能导致在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.