Charnick S B, Lauffenburger D A
Department of Chemical Engineering, University of Pennsylvania, Philadelphia 19104.
Biophys J. 1990 May;57(5):1009-23. doi: 10.1016/S0006-3495(90)82620-5.
Efficient and rapid immune response upon challenge by an infectious agent is vital to host defense. The encounter of leukocytes (white blood cells of the immune system) with their targets is the first step in this response. Analysis of the kinetics of this process is essential not only to understanding dynamic behavior of the immune response, but also to elucidating the consequences of many leukocyte functional abnormalities. The motion of leukocytes in the presence of targets typically involves a directed, or chemotactic component. These immune cells orient the direction of their motion in the presence of gradients in chemical attractants generated by pathogens. Fisher and Lauffenburger (1987. Biophys. J. 51:705-716) developed a model for macrophage/bacterium encounter in two dimensions which includes chemotaxis, and applied it to the particular system of alveolar macrophages (phagocytic leukocytes on the lung surface). Their model showed that macrophage/target encounter is likely the rate-limiting step in clearance of bacteria from the lung surface (Fisher, E. S., D. A. Lauffenburger, and R. P. Daniele. 1988. Am. Rev. Resp. Dis. 137:1129-1134). We have extended this model to analyze the effects of cell motility properties and geometric parameters on cell-target encounter in three dimensions. The differential equation governing encounter time in three dimensions is essentially the same as that in two dimensions, except for changed probability values. Our results show that more highly directed motion is necessary in three dimensions to achieve substantially decreased encounter times than in two dimensions, because of the increased search dimensionality. These general results were applied to the particular system of neutrophils operating in three dimensions in response to a bacterial challenge in connective tissue. Our results provide a plausible rationalization for both the chemotactic and chemokinetic behavior observed in neutrophils. That is, these cells exhibit in vitro a greater chemotactic bias and a more dramatic variation of speed with attractant concentration than alveolar macrophages, and our results indicate that these behaviors can have a greater influence in three-dimensional connective tissue infection situations than in two-dimensional lung surface infection cases. In addition, we show that encounter apparently is not generally the rate-limiting step in this neutrophil response. These findings have important implications for correlating in vitro measured defects in cell motility and chemotaxis properties with in vivo functions of host defense against infection.
受到感染因子攻击时，高效快速的免疫反应对宿主防御至关重要。白细胞（免疫系统的白细胞）与它们的靶标相遇是这一反应的第一步。分析这一过程的动力学不仅对于理解免疫反应的动态行为至关重要，而且对于阐明许多白细胞功能异常的后果也至关重要。在有靶标的情况下白细胞的运动通常涉及一个定向的或趋化性的成分。这些免疫细胞在病原体产生的化学引诱剂梯度存在时确定其运动方向。费舍尔和劳芬伯格（1987年。《生物物理学杂志》51:705 - 716）建立了一个二维巨噬细胞/细菌相遇的模型，其中包括趋化性，并将其应用于肺泡巨噬细胞（肺表面的吞噬性白细胞）的特定系统。他们的模型表明巨噬细胞/靶标相遇可能是从肺表面清除细菌的限速步骤（费舍尔，E.S.，D.A.劳芬伯格，和R.P.达尼埃莱。1988年。《美国呼吸与危重症医学杂志》137:1129 - 1134）。我们扩展了这个模型以分析细胞运动特性和几何参数对三维细胞 - 靶标相遇的影响。除了概率值发生变化外，三维中控制相遇时间的微分方程与二维中的基本相同。我们的结果表明，由于搜索维度增加，在三维中要实现相遇时间大幅减少比在二维中需要更高度定向的运动。这些一般结果被应用于在结缔组织中对细菌攻击做出反应的三维运作的中性粒细胞的特定系统。我们的结果为在中性粒细胞中观察到的趋化性和化学动力学行为提供了一个合理的解释。也就是说，这些细胞在体外表现出比肺泡巨噬细胞更大的趋化偏向以及随着引诱剂浓度变化更显著的速度变化，并且我们的结果表明这些行为在三维结缔组织感染情况下比在二维肺表面感染情况下可能具有更大的影响。此外，我们表明相遇显然通常不是这种中性粒细胞反应的限速步骤。这些发现对于将体外测量的细胞运动和趋化性特性缺陷与宿主抗感染的体内功能相关联具有重要意义。
