Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer

The canonical pre-2018 review of interstitial-fluid physiology. Helge Wiig is a vascular physiologist at the Department of Biomedicine at the University of Bergen in Norway, with a research line going back to the 1980s on interstitial fluid mechanics, oncotic pressure, and the regulation of tissue fluid balance. Melody A. Swartz is a bioengineer at the University of Chicago (previously at EPFL Lausanne), whose work on lymphatic transport and tumour-interstitium fluid mechanics has been foundational to the post-2000 cancer-microenvironment literature.

Published in Physiological Reviews in July 2012 — one of the highest-impact review venues in physiology — the piece is a comprehensive synthesis of the biophysical, biomechanical, and biological aspects of interstitial fluid and lymph transport in tissue physiology, pathophysiology, and immune regulation. The fifty-five-page review covers Starling forces, oncotic and hydrostatic pressure balance, interstitial flow mechanics, lymphatic capillary anatomy, the role of the interstitium in inflammation and immune- cell trafficking, and the now-substantial literature on interstitial-flow effects in tumour microenvironments. The reference list runs to over six hundred citations.

The piece sits as the pre-2018 foundation against which the Benias et al. 2018 claim of an unrecognised interstitium should be read. Wiig and Swartz document, in exhaustive detail, the existing understanding of interstitial fluid as a structured, dynamic, mechanically-active compartment with substantial physiological roles. Nothing in the 2018 Benias finding is incompatible with the Wiig-Swartz synthesis; what 2018 added was the macroscopic imaging of structures the slide-preparation method had been collapsing. The Mestres- Ventura 2019 commentary's not actually unrecognised objection draws much of its force from reviews like this one.

The stake is professional-scientific on both sides — Wiig and Swartz are senior figures whose careers have been built on the interstitial-fluid programme, and the review is a service to the field. None of the work has direct commercial application, but the cancer-microenvironment thread has substantial therapeutic implications: tumour interstitial pressure is elevated, which limits drug delivery and creates the flow-mediated invasion phenomena that Jennifer Munson and others have built clinical programmes around. Read this review before any of the post-2018 interstitium literature; it is the context that the 2018 framing did not adequately situate itself against.