Interstitial space

Abstract: The extracellular matrix (ECM) may contribute to the drug resistance of a solid tumor by preventing the penetration of therapeutic agents. We measured differences in interstitial resistance to macromolecule (IgG) motion in four tumor types and found an unexpected correspondence between transport resistance and the mechanical stiffness. The interstitial diffusion coefficient of IgG was measured in situ by fluorescence redistribution after photobleaching. Tissue elastic modulus and hydraulic conductivity were measured by confined compression of excised tissue. In apparent contradiction to an existing paradigm, these functional properties are correlated with total tissue content of collagen, not glycosaminoglycan. An extended collagen network was observed in the more penetration-resistant tumors. Collagenase treatment of the more penetration-resistant tumors significantly increased the IgG interstitial diffusion rate. We conclude that collagen influences the tissue resistance to macromolecule transport, possibly by binding and stabilizing the glycosaminoglycan component of the ECM. These findings suggest a new method to screen tumors for potential resistance to macromolecule-based therapy. Moreover, collagen and collagen-proteoglycan bonds are identified as potential targets of treatment to improve macromolecule delivery.

Abstract: While the study of the physiochemical composition and structure of the interstitium on a molecular level is a large and important field in itself, the present review centered mainly on the functional consequences for the control of extracellular fluid volume. As pointed out in section I, a biological monitoring system for the total extracellular volume seems very unlikely because a major part of that volume is made up of multiple, separate, and functionally heterogeneous interstitial compartments. Even less likely is a selective volume control of each of these compartments by the nervous system. Instead, as shown by many studies cited in this review, a local autoregulation of interstitial volume is provided by automatic adjustment of the transcapillary Starling forces and lymph flow. Local vascular control of capillary pressure and surface area, of special importance in orthostasis, has been discussed in several recent reviews and was mentioned only briefly in this article. The gel-like consistency of the interstitium is attributed to glycosaminoglycans, in soft connective tissues mainly hyaluronan. However, the concept of a gel phase and a free fluid phase now seems to be replaced by the quantitatively more well-defined distribution spaces for glycosaminoglycans and plasma protein, apparently in osmotic equilibrium with each other. The protein-excluded space, determined mainly by the content of glycosaminoglycans and collagen, has been measured in vivo in many tissues, and the effect of exclusion on the oncotic buffering has been clarified. The effect of protein charge on its excluded volume and on interstitial hydraulic conductivity has been studied only in lungs and is only partly clarified. Of unknown functional importance is also the recent finding of a free interstitial hyaluronan pool with relatively rapid removal by lymph. The postulated preferential channels from capillaries to lymphatics have received little direct support. Thus the variation of plasma-to-lymph passage times for proteins may probably be ascribed to heterogeneity with respect to path length, linear velocity, and distribution volumes. Techniques for measuring interstitial fluid pressure have been refined and reevaluated, approaching some concensus on slightly negative control pressures in soft connective tissues (0 to -4 mmHg), zero, or slightly positive pressure in other tissues. Interstitial pressure-volume curves have been recorded in several tissues, and progress has been made in clarifying the dependency of interstitial compliance on glycosaminoglycan-osmotic pressure, collagen, and microfibrils.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract: Interstitial flow plays important roles in the morphogenesis, function, and pathogenesis of tissues. To investigate these roles and exploit them for tissue engineering or to overcome barriers to drug delivery, a comprehensive consideration of the interstitial space and how it controls and affects such processes is critical. Here we attempt to review the many physical and mathematical correlations that describe fluid and mass transport in the tissue interstitium; the factors that control and affect them; and the importance of interstitial transport on cell biology, tissue morphogenesis, and tissue engineering. Finally, we end with some discussion of interstitial transport issues in drug delivery, cell mechanobiology, and cell homing toward draining lymphatics.

Abstract: We conducted a series of experiments with ultrafine particles (approximately 20 nm) and larger particles (less than 200 nm) of "nuisance" dusts to evaluate the involvement of alveolar macrophages (AM) in particle-induced lung injury and particle translocation in rats. After intratracheal instillation of both ultrafine particles and larger particles of TiO2, we found a highly increased interstitial access of the ultrafine particles combined with a large acute inflammatory reaction as determined by lung lavage parameters. An additional experiment revealed that intratracheal instillation of phagocytized ultrafine TiO2 particles (inside AM) prevented both the pulmonary inflammatory reaction and the interstitial access of the ultrafine particles. Another experiment showed that the influx of polymorphonuclear cells (PMN) into the alveolar space unexpectedly decreased with higher doses of ultrafine particles, whereas alveolar epithelial permeability (protein leakage) increased. The divergence between PMN influx into the alveolar space and changes in alveolar epithelial permeability implies that they are separate events. Pulmonary inflammatory parameters determined by lung lavage analysis correlated best with the surface area of the retained particles rather than with their mass, volume, or numbers. Because higher doses resulted in an increased interstitialized fraction of particles, we suggest that inflammatory events induced by particles in the interstitial space can modify the inflammation in the alveolar space detectable by lung lavage. Our results demonstrate the dual role of AM for modifying particle-induced lung injury, i.e., both preventing such injury and contributing to it. We conclude that the increased pulmonary toxicity of ultrafine particles is related to their larger surface area and to their increased interstitial access.(ABSTRACT TRUNCATED AT 250 WORDS)