Multi-cell Agent-based Simulation of the Microvasculature to Study the Dynamics of Circulating Inflammatory Cell Trafficking

Leukocyte trafficking through the microcirculation and into tissues is central in angiogenesis, inflammation, and the immune response. Although the literature is rich with mechanistic detail describing molecular mediators of these processes, integration of signaling events and cell behaviors within a unified spatial and temporal framework at the multi-cell tissue-level is needed to achieve a fuller understanding. We have developed a novel computational framework that combines agent-based modeling (ABM) with a network flow analysis to study monocyte homing. A microvascular network architecture derived from mouse muscle was incorporated into the ABM. Each individual cell was represented by an individual agent in the simulation. The network flow model calculates hemodynamic parameters (blood flow rates, fluid shear stress, and hydrostatic pressures) throughout the simulated microvascular network. These are incorporated into the ABM to affect monocyte transit through the network and chemokine/cytokine concentrations. In turn, simulated monocytes respond to their local mechanical and biochemical environments and make behavioral decisions based on a rule set derived from independent literature. Simulated cell behaviors give rise to emergent leukocyte rolling, adhesion, and extravasation. Molecular knockout simulations were performed to validate the model, and predictions of monocyte adhesion, rolling, and extravasation show good agreement with the independently published corresponding mouse studies. Alexander M. Bailey and Bryan C. Thorne contributed equally to this work.     

耳复康口服液对小鼠微循环障碍的影响

摘 要 目的：观察耳复康口服液对肾上腺素致急性血瘀症小鼠微循环障碍的影响。方法: 将小鼠随机分为模型组,脑得生片组（1.35 g·kg^-1）,高(30 ml·kg^-1)、中(15 ml·kg^-1)、低(7.5 ml·kg^-1)剂量耳复康口服液组,用微循环仪观察正常小鼠给药1 h后毛细血管开放数。尾静脉注射肾上腺素造成耳廓微循环障碍,观察造模后2 min小鼠的毛细血管开放数及血流情况。结果:和模型组相比,高、中、低剂量耳复康口服液对正常小鼠耳廓毛细血管开放数无明显影响(P＞0.05);与模型组相比,高、中剂量耳复康口服液可显著改善肾上腺素致小鼠耳壳微循环障碍模型微循环血流情况(P＜0.05或P<0.01),可明显对抗肾上腺素所致小鼠耳壳微循环障碍模型毛细血管网开放数的减少(P<0.05)。结论:耳复康口服液有改善微循环障碍的作用。     

The effect of clinically relevant pressure duration on sacral skin blood flow and temperature in patients after acute spinal cord injury

Sae-Sia W, Wipke-Tevis DD, Williams DA. The effect of clinically relevant pressure duration on sacral skin blood flow and temperature in patients after acute spinal cord injury.

Objective

To test the effect of clinically relevant duration of pressure loading (2h) on sacral skin blood flow (SBF) and skin temperature in subjects with spinal cord injury (SCI) within 24 to 96 hours after injury compared with subjects with acute orthopedic trauma and healthy subjects.

Design

Three-group, repeated-measures, inception cohort.

Setting

Three acute care hospitals in southern Thailand.

Participants

Convenience sample of 20 subjects with acute SCI within 24 to 96 hours after injury. Age- and sex-matched subjects with acute orthopedic trauma (n=35) and healthy subjects (n=47) served as comparison groups.

Interventions

Not applicable.

Main Outcome Measures

Sacral SBF and skin temperature were measured simultaneously by using a laser Doppler sensor and thermocouple sensor, respectively, with subjects lying in the lateral (baseline, no pressure, 30min), supine (pressure loading, 2h), and lateral position (recovery, no pressure, 90min).

Results

Baseline skin temperature was higher in subjects with acute SCI (P<.05) compared with subjects with orthopedic trauma and healthy subjects. A relative decrease in sacral SBF occurred in subjects with acute SCI (P<.01) over 2 hours of pressure loading compared with subjects with orthopedic trauma and healthy subjects. During the same time course, subjects with acute SCI had a smaller increase in sacral skin temperature compared with subjects with orthopedic trauma and healthy subjects (P<.001). During recovery, the time to the initial sacral SBF-reactive hyperemia response was shorter in subjects with acute SCI compared with subjects with orthopedic trauma (P<.001) and healthy subjects (P=.003). Additionally, the initial positive slope of the SBF reactive hyperemia response was higher in subjects with acute SCI than subjects with orthopedic trauma (P=.005) and healthy (P=.004) subjects.

Conclusions

Collectively, a negative change in SBF during pressure loading plus a shorter time to increase and greater slope for SBF after pressure release reveal microvascular dysfunction in acute SCI subjects. The clinical relevance of the protocol suggests that turning interval guidelines may require reevaluation for patients with acute SCI.     

铁蓄积骨质疏松模型凝血状态及微血栓和血管密度变化的研究

目的：了解铁蓄积骨质疏松模型中凝血状态、微血栓、微血管床及骨密度的变化,探讨骨质疏松范畴铁蓄积对凝血功能、血管方面的影响。方法：选取健康24只6月龄雄性SPF级SD大鼠,体重（250±20）g,随机分为对照组和铁蓄积组,每组12只。铁蓄积组用枸橼酸铁（ferric ammonium citrate,FAC）90 mg/kg腹腔注射干预,对照组采用等体积生理盐水腹腔注射,每周2次,干预9周。干预完成后,检测两组血清铁蛋白、凝血功能、微血栓、血管密度及股骨远端骨小梁三维形态重建和空间结构参数,并进行统计学分析。结果：铁蓄积组血清铁蛋白（136.36±35.41）μg/L较对照组（68.44±16.86）μg/L显著升高,铁蓄积组骨密度（0.167±0.024）g/cm³较对照组（0.400±0.030）g/cm³显著下降;铁蓄积组的纤维蛋白原（2.03±0.13）g/L较对照组（1.78±0.46）g/L明显升高,D-二聚体含量（534.95±31.81）ng/ml较对照组（329.02±84.99）ng/ml明显增高（P<0.05）,而凝血酶时间（39.64±2.18）s和凝血酶原时间（8.70±0.39）s较对照组（44.92±2.98）s、（9.44±0.49）s明显缩短（P<0.05）;墨汁染色后,铁蓄积组的微血管密度（17.46±2.07）%较对照组（23.81±2.98）%明显缩小（P<0.05）。HE和MSB染色均显示铁蓄积大鼠骨髓中存在微血栓,同时在心肌中也存在微血栓。结论：在铁蓄积影响的骨质疏松模型中,铁蓄积对凝血功能有显著影响,血液相对呈高凝状态,骨血管床减少,骨髓中有微血栓存在,血液的高凝状态及微血栓的形成可能是铁蓄积骨质疏松症发生的重要影响因素。     

透明质酸钠对宫腔手术患者围术期微循环及粘连状态的影响观察

目的观察透明质酸钠对宫腔手术患者围术期微循环及粘连状态的影响。方法选取2009年1月~2012年1月于本院进行宫腔手术治疗的74例患者为研究对象,将其根据随机数字表法分为对照组37例与观察组37例。对照组进行常规用药,观察组则在对照组的基础上加用透明质酸钠。比较两组患者的总粘连率及手术前后的血清FN、LN、TGF-β、VEGF、宫颈微循环指标。结果观察组的总粘连率为5.41%（2/37）,对照组为13.51%（5/37）,两组比较,差异有统计学意义（P〈0.05）;手术后2、4周,观察组的血清FN、LN、TGF-β、VEGF水平均低于对照组,观察组手术后4周的上述指标水平高于手术后2周（P均〈0.05）;手术后2、4周,观察组的宫颈血流量与宫颈血管清晰率均高于对照组（P均〈0.05）。结论透明质酸钠可有效预防宫腔手术术后粘连,可明显改善患者的围术期微循环及粘连状态。     

硝酸甘油对狗的心表冠状动脉和心肌微循环血流的影响

目的：探讨硝酸甘油(NTG)对狗心表冠状动脉和心肌微血管血流量的影响。方法：对10只雄性杂种狗静脉注射NTG后,应用心肌对比超声心动图测量心肌微血管血流量,动脉血流仪测量冠状动脉前降支血流量,超声心动图测量心脏腔径和容积。结果：NTG对心表冠状动脉和心肌微血管的血流量均无明显影响,注射NTG前后,前降支血流量为(13．91±2．91)ml/min对(14．59±4,63m)1/min；A·β值为：45．57±14．27对80．13±36．63,P均＞0．05；NTG对心率、血压、平均动脉压、中心静脉压和冠状动脉血管阻力也无明显影响。但可明显减少心脏腔径和心腔容积,尤其右心腔径和容积减少更明显；与舒张末期容积比较,NTG对心脏收缩末期容积影响更大。结论：NTG对狗的心表大冠状动脉和心肌微血管的血流量无影响,其抗心绞痛的作用可能是通过减少心脏容积和心室壁张力,减少心肌耗氧量而实现的。     

Effects of terlipressin on microcirculation of small bowel mesentery in rats with endotoxic shock

Background

Septic shock is still related to unacceptably high morbidity and mortality. Microcirculatory alteration has been demonstrated to be one important reason associated with this evolution. Vasoactive drugs are often used to restore adequate arterial pressure and tissue perfusion in septic shock. To define the roles of different drugs, the effects of terlipressin (TP) on the microcirculation of small bowel mesentery in rats with endotoxic shock were evaluated and compared with those of norepinephrine (NE).

Methods

Twenty-five adult male Wistar rats were randomized to the control (n = 5), TP (n = 10), and NE (n = 10) groups. After endotoxic shock was induced by intravenous lipopolysaccharide administration for 30 min, rats in the NE and TP groups were infused with saline 5 mL/kg/h and simultaneously given NE 4 μg/kg/min or TP 8 μg/kg/h. The mean arterial pressure, heart rate, blood gas analysis, and microvascular blood flow images of small bowel mesentery were recorded.

Results

After fluid resuscitation and vasopressor infusion, the mean arterial pressure was restored to the baseline values in the NE and TP groups. In the TP group, the heart rate was significantly lower compared with the NE group (P = 0.013). The proportion of perfused vessels and the microvascular flow index (MFI) were significantly increased; furthermore, the heterogeneity index of small vessels was markedly decreased in both the interventional groups with respect to the control group. Compared with the NE group, the MFI was significantly higher (P < 0.05) and the heterogeneity index was significantly lower (P < 0.05) in the TP group.

Conclusions

Both TP and NE improved hemodynamic and microcirculatory alterations in rats with endotoxic shock. Compared with NE, TP was more effective in promoting MFI and improving the heterogeneity of small bowel mesentery in rats.