Interstitial fluid pressure

Figure 15.7 Starling principle a summary of forces determining the bulk flow of fluid across the wall of a capillary. Hydrostatic forces include capillary pressure (Pc) and interstitial fluid pressure (PJ. Capillary pressure pushes fluid out of the capillary. Interstitial fluid pressure is negative and acts as a suction pulling fluid out of the capillary. Osmotic forces include plasma colloid osmotic pressure (np) and interstitial fluid colloid osmotic pressure (n,). These forces are caused by proteins that pull fluid toward them. The sum of these four forces results in net filtration of fluid at the arteriolar end of the capillary (where Pc is high) and net reabsorption of fluid at the venular end of the capillary (where Pc is low).

Leunig, M., Yuan, F., Menger, M.D., Boucher, Y., Goetz, A.E., Messmer, K. and Jain, R.K. (1992) Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LSI 74T in SCID mice. Cancer Res., 52, 6553-6560. 

The reverse flux of fluid from the interstitial to the vascular space (14) is caused by increased interstitial fluid pressure (12) and increased plasma protein concentration (oncotic pressure), hyperosmotemia, or both depending upon the intensity (above or below 50 -peak capacity) and duration of the exercise. Increased interstitial hydrostatic pressure and increased plasma osmotic pressures retard the fluid shift from plasma to the interstitium. Equilibrium is reached when interstitial pressure balances capillary filtration pressure (24). After cessation of exercise, restitution of plasma volume takes 40-60 minutes (21,22) unless significant dehydration is present. The immediate post-exercise hyperosmotemia, the relative hyperproteinemia, and the reduction in systemic blood pressure contribute to the restoration of plasma volume. The reduction in blood pressure, which produces a fall in local hydrostatic pressure within the capillaries of the previously active muscle, is probably the single most important factor. 

Lee, I., Boucher, Y Demhartner, T. J., and Jain, R. K. (1994) Changes in tumour blood flow, oxygenation and interstitial fluid pressure induced by pentoxifylline. Br. J. Cancer 69,492 496. 

Fig. 6. (a) Interstitial pressure gradients in the mammary adenocarcinoma R3230AC as a function of radial position. The circles ( ) represent data points (Boucher et al., 1990), and the solid line represents the theoretical profile based on our previously developed mathematical model (Jain and Baxter, 1988 Baxter and Jain, 1989). Note that the pressure is nearly uniform in most of the tumor, but drops precipitously to normal tissue values in the periphery. Elevated pressure in the central region retards the extravasation of fluid and macromolecules. In addition, the pressure drop from the center to the periphery leads to an experimentally verifiable, radially outward fluid flow. (Reproduced from Boucher et al., 1990, with permission.) (b) Microvascular pressure (MVP) in the peripheral vessels of the mammary adenocarcinoma R3230AC is comparable to the central interstitial fluid pressure (IFP) (adapted from Boucher and Jain, 1992). These results suggest that osmotic pressure difference across vessel walls is small in this tumor. 

Interstitial fluid pressures in normal tissues are approximately atmospheric or slightly sub-atmospheric, but pressures in tumors can exceed atmospheric by 10 to 30mmHg, increasing as the tumor grows. For 1-cm radius tumors, elevated interstitial pressures create an outward fluid flow of 0.1 fim/s [11]. Tumors experience high interstitial pressures because (i) they lack functional lymphatics, so that normal mechanisms for removal of interstitial fluid are not available, (ii) tumor vessels have increased permeability, and (iii) tumor cell proliferation within a confined volume leads to vascular collapse [12]. In both tissue-isolated and subcutaneous tumors, the interstitial pressure is nearly uniform in the center of the tumor and drops sharply at the tumor periphery [13]. Experimental data agree with mathematical models of pressure distribution within tumors, and indicate that two parameters are important determinants for interstitial pressure the effective vascular pressure, (defined in Section 6.2.1), and the hydraulic conductivity ratio, (also defined in Section 6.2.1) [14]. The pressure at the center of the tumor also increases with increasing tumor mass. 

Hargens A.R. 1986. Interstitial fluid pressure and lymph flow. In R. Skalakand S. Chien (Eds.), Handbook ofBioengineeringyYol. 19, pp. 1-35, New York, McGraw-HiU. 

Wiig H. 1990. Evaluation of methodologies for measurement of interstitial fluid pressure (Pi) physiological implications of recent Pi data. Crit. Rev. Biomed. Eng. 18 27. 

Another feature of tumors that can have a major impact on the distribution of targeted radiotherapeutics is tumor interstitial fluid pressure. Interstitial fluid pressure results in a pressure gradient that can inhibit the delivery of molecules from the plasma to the extracellular fluid in central regions of a tumor. Tliis pressure gradient is not present in normal tissues because they have a lymphatic system however, tumors do not, creating an additional barrier that must be overcome. Experimental evidence of an elevated interstitial pressure in murine tumor models has been reported by Boucher et al. (1990). As expected, the effect was most apparent at the tumor periphery. Using a mathematical model, the magnitude of this outward convection fluid flow was predicted to be 0.1-0.2 pm/s (Jain and Baxter 1988). 

Interstitial Fluid Pressure and Convective Currents into the Interstitial Space of Tumors 57... 

After seeping copiously out of the highly permeable tumor microvessels—an equilibrium is reached when the hydrostatic and oncotic pressures within the microvessels and the respective interstitial pressures become equal—fluid accumulates in the tumor extracellular matrix and a high interstitial fluid pressure (IFP) builds up in sohd tumors (Young et al. 1950 Gutmann et al. 1992 Less et al. 1992 Milosevic et al. 2001,2004). 

Table 43. Interstitial fluid pressure in normal tissues and in human tumors ...

Type of tissue Mean interstitial fluid pressure (mmllg) [range] Authors... 

Fyles A, Milosevic M, Pintilie M, Syed A, Levin W, Manchul L, Hill RP (2006) Long-term performance of interstitial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 80 132-137 Fyles A, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Sun A, Chapman W, Levin W, Manchul L, Keane T, Hill RP (1998) Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol 48 149-156... 

Haider MA, Milosevic M, Fyles A, Sitartchouk I, Yeung I, Henderson E, Lockwood G, Lee TY, Roberts TPL (2005) Assessment of the tumor microenvironment in cervix cancer using dynamic contrast enhanced CT, interstitial fluid pressure and oxygen measurements. Int J Radiat Oncol Biol Phys 62 1100-1107... 

Heldin C-H, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nature 4 806-813... 

Lunt SJ, Kalliomaki TMK, Brown A, Yang VX, Milosevic M, Hill RP (2008) Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours. BMC Cancer 8 2... 

Milosevic M, Fyles A, Haider M, Hedley D, Hill R (2004) The human tumor microenvironment invasive (needle) measurement of oxygen and interstitial fluid pressure (IFP). Sem Radiat Oncol 14 249-258... 

Milosevic M, Fyles A, Hedley D, Pintilie M, Levin W, Manchul L, Hill R (2001a) Interstitial fluid pressure predicts survival in patients with cervic cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res 61 6400-6405... 

Milosevic MF, Fyles AW, Wong R, Pintilie M, Kavanagh M-C, Levin W, Manchul LA, Keane TJ, Hill RP (1998) Interstitial fluid pressure in cervical carcinoma. Cancer 82 2418-2426... 

Nathanson SD, Nelson L (1994) Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Ann Surg Oncol 1 333-338... 

Netti PA, Baxter LT, Boucher Y, Skalak R, Jain RK (1995) Time-dependent behavior of interstitial fluid pressure in solid tumors Implication for drug delivery. Cancer Res 55 5451-5458... 

Sundstrom S, Bremnes R, Aasebo U, et al (2004) Hypofrac-tionated palliative radiotherapy (17 Gy per 2 fractions) in advanced non-small cell lung carcinoma is comparable to standard fractionation for symptom control and survival a national phase 111 trial. J Clin Oncol 22 801-810 Taghian AG, Abi-Raad R, Assaad SI, et al (2005) Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy clinical implications. J Clin Oncol 23 1951-1961... 

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