Fractal-like kinetics of intracellular enzymatic reactions: a chemical framework of endotoxin tolerance and a possible non-specific contribution of macromolecular crowding to cross-tolerance.
Fractal-like kinetics of intracellular enzymatic reactions: a chemical framework of endotoxin tolerance and a possible non-specific contribution of macromolecular crowding to cross-tolerance.
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DOI：
10.1186/1742-4682-10-55
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发表时间：
2013-09-14
影响因子：
--
通讯作者：
Calin GA
中科院分区：
文献类型：
--
作者：
Vasilescu C;Olteanu M;Flondor P;Calin GA
对内毒素（LPS）的应答和随后的信号转导导致先天性免疫细胞产生细胞因子如肿瘤坏死因子-α（TNF-α）。用内毒素预处理的细胞或生物体进入短暂的低反应性状态，称为内毒素耐受（ET），其代表负预处理的特定情况。尽管最近在理解ET的分子基础方面取得了进展，但对于ET的主要机制和更复杂的交叉耐受性病例尚未达成共识。在这项研究中，我们研究了大分子拥挤（MMC）和分形动力学（FLK）的LPS信号机制的细胞内酶反应的后果。我们假设这种特殊类型的酶动力学可以解释ET现象的发展。我们在本研究中的目的是表征ET的化学动力学框架，并确定是否分形动力学解释，至少部分，ET。我们开发了一个常微分方程（ODE）的数学模型，考虑到MMC和LPS信号机制之间的联系，导致ET。我们提出了细胞内分形环境（MMC）有助于ET，并开发了两个数学模型的酶动力学：一个基于Kopelman的分形动力学框架，另一个基于Savageau的幂律模型。Kopelman的模型提供了分形细胞内环境（MMC）对ET的潜在影响的良好图像。Savageau幂律模型也部分解释了ET。计算机模拟结果支持MMC和FLK可能在ET中起作用的假设。该模型突出了组织的细胞内环境，MMC和LPS信号机制导致ET之间的联系。我们基于FLK的模型并没有最大限度地减少许多负面调节因素的作用。它只是提请注意这样一个事实，即大分子拥挤可以通过施加几何约束和细胞内反应的特定化学动力学来显著地促进ET的诱导。
The response to endotoxin (LPS), and subsequent signal transduction lead to the production of cytokines such as tumor necrosis factor-α (TNF-α) by innate immune cells. Cells or organisms pretreated with endotoxin enter into a transient state of hyporesponsiveness, referred to as endotoxin tolerance (ET) which represents a particular case of negative preconditioning. Despite recent progress in understanding the molecular basis of ET, there is no consensus yet on the primary mechanism responsible for ET and for the more complex cases of cross tolerance. In this study, we examined the consequences of the macromolecular crowding (MMC) and of fractal-like kinetics (FLK) of intracellular enzymatic reactions on the LPS signaling machinery. We hypothesized that this particular type of enzyme kinetics may explain the development of ET phenomenon. Our aim in the present study was to characterize the chemical kinetics framework in ET and determine whether fractal-like kinetics explains, at least in part, ET. We developed an ordinary differential equations (ODE) mathematical model that took into account the links between the MMC and the LPS signaling machinery leading to ET. We proposed that the intracellular fractal environment (MMC) contributes to ET and developed two mathematical models of enzyme kinetics: one based on Kopelman’s fractal-like kinetics framework and the other based on Savageau’s power law model. Kopelman’s model provides a good image of the potential influence of a fractal intracellular environment (MMC) on ET. The Savageau power law model also partially explains ET. The computer simulations supported the hypothesis that MMC and FLK may play a role in ET. The model highlights the links between the organization of the intracellular environment, MMC and the LPS signaling machinery leading to ET. Our FLK-based model does not minimize the role of the numerous negative regulatory factors. It simply draws attention to the fact that macromolecular crowding can contribute significantly to the induction of ET by imposing geometric constrains and a particular chemical kinetic for the intracellular reactions.
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影响因子：
4.3
作者：
An GC;Faeder JR
通讯作者：
Faeder JR
影响因子：
4.4
作者：
Cuschieri, J;Gourlay, D;Maier, RV
通讯作者：
Maier, RV
影响因子：
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作者：
Minton, Allen P.
通讯作者：
Minton, Allen P.
影响因子：
2.9
作者：
Grima, Ramon;Schnell, Santiago
通讯作者：
Schnell, Santiago
影响因子：
--
作者：
Długosz M;Trylska J
通讯作者：
Trylska J