INTERSTITIAL FLUID AND LYMPH FORMATION AND TRANSPORT: PHYSIOLOGICAL REGULATION AND ROLES IN INFLAMMATION AND CANCER

The interstitium describes the fluid,proteins, solutes, and the extracellular matrix (ECM) that comprise the cellular micro-environment in tissues. Its alterations are fundamental to changes in cell function ininflammation, pathogenesis, and cancer. Interstitial fluid (IF) is created by transcapillary filtrationand cleared by lymphatic vessels. Herein we discuss the biophysical, biomechanical, and functionalimplications of IF in normal and pathological tissue states from both fluid balance and cell functionperspectives. We also discuss analysis methods to access IF, which enables quantification of thecellular microenvironment; such methods have demonstrated, for example, that there can bedramatic gradients from tissue to plasma during inflammation and that tumor IF is hypoxic andacidic compared with subcutaneous IF and plasma. Accumulated recent data show that IF and itsconvection through the interstitium and delivery to the lymph nodes have many and diversebiological effects, including in ECM reorganization, cell migration, and capillary morphogenesis aswell as in immunity and peripheral tolerance. This review integrates the biophysical, biomechanical,and biological aspects of interstitial and lymph fluid and its transport in tissue physiology, patho-physiology, and immune regulation.