Elevated Interstitial Pressure Research Articles

Haemodynamic and Transport Barriers to the Treatment of Solid Tumours

The efficacy in cancer treatment of novel therapeutic agents such as monoclonal antibodies, cytokines and effector cells has been limited by their inability to reach their target in vivo in adequate quantities. Molecular and cellular biology of neoplastic cells alone has failed to explain the nonuniform uptake of these agents. This is not surprising since a solid tumour in vivo is not just a collection of cancer cells. In fact, it consists of two extracellular compartments: vascular and interstitial. Since no blood-borne molecule or cell can reach cancer cells without passing through these compartments, the vascular and interstitial physiology of tumours has received considerable attention in recent years. Three physiological factors responsible for the poor localization of macromolecules in tumours have been identified: (i) heterogeneous blood supply, (ii) elevated interstitial pressure, and (iii) large transport distances in the interstitium. The first factor limits the delivery of blood-borne agents to well-perfused regions of a tumour; the second factor reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumour periphery which opposes the inward diffusion; and the third factor increases the time required for slowly moving macromolecules to reach distal regions of a tumour. Binding of the molecule to an antigen further lowers the effective diffusion rate by reducing the amount of mobile molecule. Although the effector cells are capable of active migration, peculiarities of the tumour vasculature and interstitium may also be responsible for poor delivery of lymphokine activated killer cells and tumour infiltrating lymphocytes in solid tumours. Due to micro- and macroscopic heterogeneities in tumours, the relative magnitude of each of these physiological barriers would vary from one location to another and from one day to the next in the same tumour, and from one tumour to another. If the genetically engineered macromolecules and effector cells, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, strategies must be developed to overcome or exploit these barriers. Some of these strategies are discussed, and situations wherein these barriers may not be a problem are outlined. Finally, some therapies where the tumour vasculature of the interstitium may be a target are pointed out.

Vascular and interstitial barriers to delivery of therapeutic agents in tumors

The efficacy in cancer treatment of novel therapeutic agents such as monoclonal antibodies, cytokines and effector cells has been limited by their inability to reach their target in vivo in adequate quantities. Molecular and cellular biology of neoplastic cells alone has failed to explain the nonuniform uptake of these agents. This is not surprising since a solid tumor in vivo is not just a collection of cancer cells. In fact, it consists of two extracellular compartments: vascular and interstitial. Since no blood-borne molecule or cell can reach cancer cells without passing through these compartments, the vascular and interstitial physiology of tumors has received considerable attention in recent years. Three physiological factors responsible for the poor localization of macromolecules in tumors have been identified: (i) heterogeneous blood supply, (ii) elevated interstitial pressure, and (iii) large transport distances in the interstitium. The first factor limits the delivery of blood-borne agents to well-perfused regions of a tumor; the second factor reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumor periphery which opposes the inward diffusion; and the third factor increases the time required for slowly moving macromolecules to reach distal regions of a tumor. Binding of the molecule to an antigen further lowers the effective diffusion rate by reducing the amount of mobile molecule. Although the effector cells are capable of active migration, peculiarities of the tumor vasculature and interstitium may be also responsible for poor delivery of lymphokine activated killer cells and tumor infiltrating lymphocytes in solid tumors. Due to micro- and macroscopic heterogeneities in tumors, the relative magnitude of each of these physiological barriers would vary from one location to another and from one day to the next in the same tumor, and from one tumor to another. If the genetically engineered macromolecules and effector cells, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, strategies must be developed to overcome or exploit these barriers. Some of these strategies are discussed, and situations wherein these barriers may not be a problem are outlined. Finally, some therapies where the tumor vasculature or the interstitium may be a target are pointed out.

Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection

A general theoretical framework for transvascular exchange and extravascular transport of fluid and macromolecules in tumors is developed. The resulting equations are applied to the most simple case of a homogeneous, alymphatic tumor, with no extravascular binding. Numerical simulations show that in a uniformly perfused tumor the elevated interstitial pressure is a major cause for heterogeneous distribution of nonbinding macromolecules, because it (i) reduces the driving force for extravasation of fluid and macromolecules in tumors, (ii) results in nonuniform filtration of fluid and macromolecules from blood vessels, and (iii) leads to experimentally verifiable, radially outward convection which opposes the inward diffusion. The models are used to predict the interstitial pressure, interstitial fluid velocity, and concentration profiles as a function of radial position and tumor size. The model predictions agree with the following experimental data: (i) the interstitial pressure in a tumor is lowest at the periphery of the tumor and increases towards the center; (ii) the radially outward fluid velocity predicted by the fluid transport model is of the same order of magnitude as that measured in tissue-isolated tumors; and (iii) the concentration of macromolecules is higher in the periphery than in the center of tumors at short times postinjection; however, at later times the peripheral concentration is less than the concentration in the center. This work shows that in addition to the heterogeneous distribution of blood supply, hindered interstitial transport, and rapid extravascular binding of macromolecules (e.g., monoclonal antibodies), the elevated interstitial pressure plays an important role in determining the penetration of macromolecules into tumors. If the genetically engineered macromolecules are to fulfill their clinical promise, methods must be developed to overcome these physiological barriers in tumors.

Transient Blindness in Pre-Eclakpsia: Two Cases and A Review of the Literature

Two patients with severe pre-eclampsia in the third trimester of pregnancy developed sudden blindness. Physical examination and computed tomography indicated a central cause, most likely cerebral edema. Swan-Ganz catheterisation revealed a low cardiac preload and a markedly elevated afterload. Following pharmacologic reduction of the afterload the blindness disappeared completely.On the basis of the two cases presented and a review of the pertinent literature we conclude that temporary cortical blindness in patients with severe pre-eclampsia may usually be attributed to focal cerebral edema. It seems likely that a combination of high cerebral arterial pressure, leading to disruption of capillary tight junctions, with an elevated interstitial cerebral colloid osmotic pressure constitutes the main determinant of fluid leakage into cerebral tissue. Treatment should consist of gradual pharmacologic reduction of mean arterial blood pressure.

The deaeration of fine powders

A theoretical analysis has been made of the rate of deaeration of a dilated bed of fine particles. The work is relevant to the phenomenon of flooding, since flooding is said to occur only when the material is dilated. This analysis is more general than previous analyses, and makes allowance for the change in bed depth as well as the change in bulk properties occurring during deaeration. A test case has shown that deaeration is a two-stage process. In the first stage, settlement of the bed occurs with the voidage approaching its final value fairly rapidly. At the end of this stage, elevated interstitial pressures still occur within the bed and these subsequently decay over a longer time-scale. Generalised predictions are given for the time-scale of the deaeration process as functions of the bed geometry and material properties.

Renal interstitial pressure in mineralocorticoid escape.

Studies were performed in normal and DOCA-treated rats to determine renal hydrostatic pressures within superficial peritubular capillaries, the vasa recta, and renal interstitium during mineralocorticoid escape to test the hypothesis that mineralocorticoid escape is associated with elevated renal interstitial hydrostatic pressure. Fractional sodium excretion was greater in the DOCA-treated rats (3.20 +/- 0.51%) compared with control rats (1.23 +/- 0.12%) with no difference in glomerular filtration rate and renal blood flow between the two groups. Superficial peritubular capillary hydrostatic pressure (13.4 +/- 0.6 vs. 8.3 +/- 0.3 mmHg), vasa recta hydrostatic pressure (13.8 +/- 0.5 vs. 9.0 +/- 0.4 mmHg), renal interstitial hydrostatic pressure (9.8 +/- 0.4 vs. 4.5 +/- 0.4 mmHg), and arterial pressure (145 +/- 6 vs. 120 +/- 7 mmHg) were greater in the DOCA-treated compared with the control rats. These studies establish that mineralocorticoid escape is characterized by high renal interstitial hydrostatic pressure.

Does interstitial pressure oppose lung water formation?

The factors affecting the formation of pulmonary edema have been the subject of study and controversy for many years. In 1896, Starling [ 151 defined the relationship between the hydrostatic and oncotic forces regulating fluid flow across the capillary membrane. The protection of the lung from edema formation is necessary to maintain sufficient gas exchange to ensure normal oxygen delivery. Various “safety factors” [3, 161 have been theorized to be acting to protect the lung from increases in the extravascular lung water (EVLW). Interstitial pressure (IP) has been postulated as one of the potential safety factors [3, 161. Previous studies have found elevated IP in pulmonary edema [6, 10, 11, 12]. We asked the question, as EVLW rises during the development of pulmonary edema due to increased hydrostatic pressure, does IP rise quickly to oppose further EVLW accumulation?

Parenchymal striations in renal vein thrombosis: arteriographic demonstration

Arteriographic visualization of parenchymal striation in renal vein thrombosis is reported for the first time. The striations correspond to the location and orientation of the peritubular capillary beds of the renal cortex, which are in linear continuity with the vasa recta of the medulla. Opacification of these vascular structures in a cadaver kidney produced the same striation pattern. One possible physiologic explanation is that renal vein thrombosis causes elevated renal interstitial pressure which slows tubular urine flow. This altered intrarenal state prevents opacification of renal tubular structures while adjacent peritubular vascular structures are opacified, thereby producing a pattern of alternating striation.

Effect of elevated interstitial pressure on the renal cortical hemodynamics.

The influence of renal interstitial pressure on the resistance pattern within the superficial cortical vasculature has been investigated from determinations of 1) the glomerular blood flow eith a modified microsphere technique and 2) the intravascular hydrostatic pressures. Interstitial pressure was monitored via a 50 mum PVC-catheter placed into the subcapsular interstitial space. Two conditions were analyzed viz. a) elevation of uretheral pressure to 20 mm Hg and b) venous stasis to 10-15 mm Hg. Both conditions produced an increase in the interstitial pressure from 1-2 mm Hg to about 5 mm Hg as well as an increased hilar lymph flow and protein flow of about the same size. The vascular reactions were different, however. Uretheral stasis (but not the stasis of a single nephron) produced a decreased resistance in the afferent arteriolae with a concomitant increae in the pressures in the glomerular capillaries, and the peritobular capillary network. In contrast, venous stasis produced only small changes in the parameters studied but for the obvious rise in the peritubular capillary pressure. The results suggest that factors other than the interstitial pressure are governing the afferent vascular tone; the tubular wall tension might be one of these factors.

Redistribution of renal cortical blood flow during ureteral occlusion and renal venous constriction.

SummaryThe distribution of blood flow between four zones of the canine renal cortex was measured by the tracer-labeled microsphere technique. The effect of ureteral occlusion on cortex zone flow distribution was studied during saline diuresis, mannitol diuresis, and ethacrynic acid diuresis. Renal venous constriction was performed in oliguric animals. The venous pressure was elevated to an average of 62.2 mm Hg, the highest level at which renal blood flow remained constant. Both ureteral occlusion and renal venous constriction resulted in a redistribution of flow from the most superficial cortex to deeper cortex zones. We infer that the redistribution reflects the renal circulatory response to elevated renal interstitial pressure since it was produced by both renal venous constriction and ureteral occlusion and was independent of the type of accompanying diuresis. This redistribution was found to be indistinguishable from that caused by reduction in renal arterial pressure. This suggests that a common mec...

Hydrostatic pressures in peritubular capillaries and tubules in the rat kidney

Hydrostatic pressures in peritubular capillaries and tubules in the rat kidney

A reversible concentrating defect in predominantly unilateral renal Hodgkin's disease

The function of each kidney was assessed separately in a patient with predominantly unilateral renal involvement by Hodgkin's disease. Initially, the greatly enlarged diseased kidney exhibited diminished concentrating ability, and its glomerular filtration rate was only 6 per cent of the contralateral value. After a three month course of cytotoxic chemotherapy, utilizing a combination of four drugs, the size of the affected kidney decreased substantially. Although the glomerular filtration rates on both sides remained unchanged, concentrating ability improved markedly on the diseased side. In addition, the relative rates of uric acid and potassium excretion normalized, as compared to the contralateral kidney. These data imply that the renal concentrating mechanism in disease may be affected by intrarenal parameters extrinsic to the remaining functioning nephrons, possibly by such potentially reversible factors as cellular infiltrate, edema and elevated renal interstitial pressure.