Human Lung Interstitium Forms a Continuous Body-Wide Communication Network

The interstitium — the fluid-filled connective tissue spaces permeating virtually every organ — has gained increasing recognition as a structured, body-wide network rather than a passive filler between cells. Prior work in colon, skin, and liver demonstrated spatial continuity of fascial interstitial spaces across tissue layers and between organs via hyaluronic acid (HA) staining. This study asked whether the same applies to the lung and whether pulmonary interstitial spaces connect outward to the broader body-wide network.

The research team studied archival lung lobectomy specimens from nine patients (six females, three males; mean age 53 ± 16.5 years) containing normal tissue spanning all major anatomical units. Mouse lung tissue served as a comparative model. Multiplex immunohistochemical panels targeted HA, CD34, and vimentin to highlight interstitial architecture, and a second panel added podoplanin (D2-40) to delineate lymphatics alongside vasculature and interstitium. Sizes of extracellular accumulations — termed accumulations of perivascular/perineural spaces (APP) — were also measured.

HA staining was continuous across all five canonical pulmonary compartments: alveolar walls, subpleural connective tissue, centrilobular peribronchovascular compartment, interlobular septal compartment, and the axial peribronchovascular zone of the hilum. This continuity was reproduced in murine tissue. Crucially, HA staining and APP distribution confirmed that the pulmonary interstitium connects to extrapulmonary structures via perineurial sheaths and vascular adventitia — the same conduits previously identified as linking organs in the body-wide interstitial network. APP distribution mapped closely onto established superficial and deep lymphatic drainage routes of the lung.

These findings carry broad physiological and pathobiological implications. A continuously connected interstitial network provides anatomical plausibility for how inflammatory cells and mediators, malignant cells, and infectious agents could travel within and beyond the lung without relying solely on conventional vascular or lymphatic channels. The perineurial and adventitial connections raise the possibility that the lung interstitium participates in the lung–brain axis, and that microbiome-derived signals could traverse interstitial routes. Understanding these pathways could reshape models of pulmonary fibrosis, metastatic spread, pneumonia progression, and systemic inflammatory syndromes.

Caveats include the relatively small, retrospective archival cohort and the inherent limitations of cross-sectional histology, which cannot directly demonstrate fluid flow or directionality. The study is descriptive and anatomical; functional validation of interstitial transport along these pathways remains to be established in dynamic or in vivo models.