Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy.
Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy.
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发表时间：
1994-11
期刊：
影响因子：
11.2
通讯作者：
Martin Gr;R. Jain
中科院分区：
文献类型：
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作者：
Martin Gr;R. Jain
肿瘤间质pH及其调节在肿瘤治疗中起着重要作用。目前的体内pH测量技术是有创的和/或提供较差的空间分辨率。因此，没有关于正常或肿瘤组织中血管周围间质pH梯度的数据。我们将荧光比率成像显微镜技术与兔耳腔制备相结合，在活体组织中以高分辨率测量了正常组织和肿瘤(VX2癌)组织的间质pH梯度。我们方法的优点包括能够连续几周跟踪同一位置的PH值，并将这些测量与局部血流和血管结构联系起来。结果表明：(1)肿瘤间质pH值(6.75U；N=6，n=324)显著低于正常(7.23；N=5，n=274)(P<；0.001)。肿瘤间质中酸度的增加与先前报道的关于该肿瘤的数据一致；(B)关于正常组织中的pH空间梯度，在距离血管50微米的距离内，间质的pH降低了约0.32个pH单位，而在肿瘤组织中，在相同的距离内，间质的pH降低了约0.13个单位。尽管正常组织管壁附近的pH梯度比肿瘤组织大，但正常组织的质子浓度梯度小于肿瘤组织。来自血管的质子浓度从0-50微米大约增加了4.5×10(-8)M，而在肿瘤组织中为5.7×10(-8)M；(C)简单的一维扩散-反应模型表明，肿瘤组织产生质子的速度比正常组织大65-100%；(D)高血糖(6g/kg)或高二氧化碳(10%CO2)引起的时间动力学可行性研究导致组织间隙pH显著降低(P<；0.05)。在高血糖期间，肿瘤组织的pH在90分钟内下降了0.2个pH单位以上，而正常组织的pH保持不变。高碳酸血症使肿瘤组织的pH值显著降低了约0.3个pH单位。我们对高血糖和高碳酸血症的有限研究与以前发表的研究一致，并证明了荧光比率成像显微镜测量间质pH的空间和时间变化的能力。荧光比率成像显微镜应该允许对新的pH调节剂进行非侵入性评估，并在可以观察组织表面的组织制备中提供关于肿瘤病理生理学的独特机制信息。
The tumor interstitial pH and its modification play a significant role in cancer treatment. Current in vivo pH measurement techniques are invasive and/or provide poor spatial resolution. Therefore, there are no data on perivascular interstitial pH gradients in normal or tumor tissue. We have optically measured interstitial pH gradients with high resolution in normal and tumor (VX2 carcinoma) tissue in vivo by combining a fluorescence ratio imaging microscopy technique and the rabbit ear chamber preparation. The strengths of our approach include the ability to follow pH in the same location for several weeks and to relate these measurements to local blood flow and vascular architecture. Our results show: (a) tumor interstitial pH (6.75 units; N = 6 animals, n = 324 measurements) is significantly (P < 0.001) less than normal interstitial pH (7.23; N = 5, n = 274). This increased acidity in the tumor interstitium is in agreement with the previously reported data on this tumor; (b) with respect to pH spatial gradients in normal tissue, the interstitial pH decreased by approximately 0.32 pH units over a distance of 50 microns away from the blood vessel, while in tumor tissue, interstitial pH decreased by approximately 0.13 units over the same distance. Although the pH gradient near the vessel wall was steeper in normal tissue compared to tumor, the proton concentration gradient in normal tissue was less than that in the tumor. The approximate increase in proton concentration from 0-50 microns from the vessel was 4.5 x 10(-8)M in normal versus 5.7 x 10(-8)M in tumor tissue; (c) a simple one-dimensional diffusion-reaction model suggested that tumor tissue was producing protons at a rat 65-100% greater than normal tissue; (d) feasibility studies of temporal dynamics resulting from hyperglycemia (6 g/kg) or hypercapnia (10% CO2) led to significant (P < 0.05) interstitial pH reductions. During hyperglycemia, pH dropped by more than 0.2 pH units in about 90 min in tumor tissue but remained constant in normal tissue. Hypercapnia dramatically reduced pH by approximately 0.3 pH units in tumor tissue. Our limited studies on hyperglycemia and hypercapnia are in agreement with the previously published studies and demonstrate the capability of fluorescence ratio imaging microscopy to measure spatial as well as temporal changes in interstitial pH. Fluorescence ratio imaging microscopy should permit noninvasive evaluation of new pH-modifying agents and offer unique mechanistic information about tumor pathophysiology in tissue preparations where the surface of the tissue can be observed.