Tight junction structure, function, and assessment in the critically ill: a systematic review

Abstract

Background: Epithelial and endothelial barrier integrity, essential for homeostasis, is maintained by cellular boarder structures known as tight junctions (TJs). In critical illness, TJs may become disrupted, resulting in barrier dysfunction manifesting as capillary leak, pulmonary edema, gut bacterial translocation, and multiple organ failure. We aim to provide a clinically focused overview of TJ structure and function and systematically review and analyze all studies assessing markers of endothelial and epithelial TJ breakdown correlated with clinical outcomes in critically ill humans.

Methods: We systematically searched MEDLINE, EMBASE, and PubMed. Additional articles were identified by targeted searches. We included studies that looked at the relationship between biomarkers of endothelial or epithelial TJ structure or function and critical illness. Results were qualitatively analyzed due to sample size and heterogeneity.

Results: A total of 5297 abstracts met search criteria, of which 150 articles met requirements for full text review. Of these, 30 studies met inclusion criteria. Fifteen of the 30 reports investigated proteins of endothelial tight junctions and 15 investigated epithelial TJ markers, exclusively in the gastrointestinal epithelium. No studies investigated TJ-derived proteins in primary cardiac or pulmonary pathology.

Conclusions: TJ integrity is essential for homeostasis. We identified multiple studies that indicate TJs are disrupted by critical illness. These studies highlight the significance of barrier disruption across many critical disease states and correlate TJ-associated markers to clinically relevant outcomes. Further study on the role of multiple tissue-specific claudins, particularly in the setting of respiratory or cardiac failure, may lead to diagnostic and therapeutic advances.

Systematic review registration: This systematic review is registered in the PROSPERO database: CRD42017074546 .

Keywords: Capillary leak; Cellular permeability; Critical care; Endothelial cells; Epithelial cells; Tight junctions.

Fig. 1

Many different cell types utilize tight junction (TJ)-dependent barriers. TJs are comprised of occludin (also called tricellulin), junctional adhesion molecules (JAMs), and claudins. Variability in the claudin component (claudin-1 through -24) dictates the permselectivity of the barrier while JAMs may also vary (JAM-A, -B, or -C), although their functional impact is less well understood. TJs are linked to the cytoskeleton through adapter proteins like zonula occludens (ZO-1, -2, and -3). a Columnar or cuboidal epithelia found in the upper airway, GI tract and parts of the nephron (proximal and distal tubules and collecting duct) form apical interlocking bands of tight junctions. b Squamous epithelia, such as in the lung, Bowman’s capsule and thin segments of the nephron, have interspaced TJs without regard to cell polarity. c Simple squamous endothelia of blood vessels, blood-brain barrier, and lymphatic vessels have irregularly spaced TJs that vary greatly in number based on tissue and vascular segment specific microenvironments

Fig. 2

Search strategy and results of the systematic review of the literature