Pulmonary gas exchange critically depends upon the hydration state and the thinness of the interstitial tissue layer within the alveolo-capillary barrier. In the interstitium, fluid freely moving within the fibrous extracellular matrix equilibrates with water chemically interacting with hyaluronic acid and proteoglycans, the non-fibrillar components of the matrix. The integrity of the macromolecular assembly of the tissue matrix is required in all processes involved in establishing and maintaining the adequate interstitial tissue fluid volume, by providing: (a) a stiff three dimensional fibrous scaffold, functioning as an efficient safety factor to oppose fluid filtration into the tissue and preventing tissue fluid accumulation; (b) a restrictive perivascular and interstitial sieve with respect to plasma proteins; (c) a mechanical support to initial lymphatics. Therefore, disturbances of the deposition and/or turnover of the matrix and/or of its three dimensional architecture and composition are invariably accompanied by profound changes of the steady state tissue fluid dynamics, eventually evolving towards severe lung disease.