An Gary, Nieman Gary, Vodovotz Yoram
Int J Burns Trauma. 2012;2(1):1-10. Epub 2012 Feb 1.
Trauma, often accompanied by hemorrhage, is a leading cause of death worldwide, often leading to inflammation-related late complications that include sepsis and multiple organ failure. These secondary complications are a manifestation of the complexity of biological responses elicited by trauma/hemorrhage, responses that span most, if not all, cell types, tissues, and organ systems. This daunting complexity at the patient level is manifest by the near total dearth of available therapeutics, and we suggest that this dire condition is due in large part to the lack of a rational, systems-oriented framework for drug development, clinical trial design, in-hospital diagnostics, and post-hospital care. We have further suggested that mechanistic computational modeling can form the basis of such a rational framework, given the maturity of systems biology/computational biology. Herein, we briefly summarize the state of the art of these approaches, and highlight the biological insights and novel hypotheses derived from these approaches. We propose a rational framework for transitioning through the currently fragmented process from identification of biological networks that are potential therapeutic targets, through clinical trial design, to personalized diagnosis and care. Insights derived from systems and computational biology in trauma and sepsis include the centrality of Damage-Associated Molecular Pattern molecules as drivers of both beneficial and detrimental inflammation, along with a novel view of multiple organ dysfunction as a cascade of containment failures with distinct implications for therapy. Finally, we suggest how these insights might be best implemented to drive transformational change in the fields of trauma and sepsis.
创伤，常伴有出血，是全球主要的死亡原因，常导致包括败血症和多器官功能衰竭在内的与炎症相关的晚期并发症。这些继发性并发症是创伤/出血引发的生物反应复杂性的一种表现，这种反应涉及大多数（如果不是全部）细胞类型、组织和器官系统。在患者层面，这种令人望而生畏的复杂性表现为几乎完全缺乏可用的治疗方法，我们认为这种严峻状况在很大程度上是由于缺乏一个合理的、以系统为导向的药物研发、临床试验设计、院内诊断和院后护理框架。鉴于系统生物学/计算生物学的成熟，我们进一步提出，机制计算建模可以构成这样一个合理框架的基础。在此，我们简要总结这些方法的现状，并突出从这些方法中获得的生物学见解和新假设。我们提出了一个合理框架，用于从识别作为潜在治疗靶点的生物网络，经过临床试验设计，到个性化诊断和护理，贯穿当前碎片化的过程。创伤和败血症领域中系统和计算生物学的见解包括损伤相关分子模式分子作为有益和有害炎症驱动因素的核心地位，以及将多器官功能障碍视为一系列遏制失败的新观点，这对治疗具有不同的意义。最后，我们建议如何最好地实施这些见解，以推动创伤和败血症领域的变革性变化。
