Integrin α β can substitute for collagen-binding β -integrins in vivo to maintain a homeostatic interstitial fluid pressure.

NEW FINDINGS

What is the central question of this study? Collagen-binding β -integrins function physiologically in cellular control of dermal interstitial fluid pressure (P ) in vivo and thereby participate in control of extravascular fluid volume. During anaphylaxis, simulated by injection of compound 48/80, integrin α β takes over this physiological function. Here we addressed the question whether integrin α β can replace collagen-binding β -integrin to maintain a long-term homeostatic P . What is the main finding and its importance? Mice lacking the collagen-binding integrin α β show a complex dermal phenotype with regard to the interstitial physiology apparent in the control of P . Notably dermal P is not lowered with compound 48/80 in these animals. Our present data imply that integrin α β is the likely candidate that has taken over the role of collagen-binding β -integrins for maintaining a steady-state homeostatic P . A better understanding of molecular processes involved in control of P is instrumental for establishing novel treatment regimens for control of oedema formation in anaphylaxis and septic shock.

ABSTRACT

Accumulated data indicate that cell-mediated contraction of reconstituted collagenous gels in vitro can serve as a model for cell-mediated control of interstitial fluid pressure (P ) in vivo. A central role for collagen-binding β -integrins in both processes has been established. Furthermore, integrin α β takes over the role of collagen-binding β -integrins in mediating contraction after perturbations of collagen-binding β -integrins in vitro. Integrin α β is also instrumental for normalization of dermal P that has been lowered due to mast cell degranulation with compound 48/80 (C48/80) in vivo. Here we demonstrate a role of integrin α β in maintaining a long term homeostatic dermal P in mice lacking the collagen-binding integrin  α β (α11 mice). Measurements of P were performed after circulatory arrest. Furthermore, cell-mediated integrin α β -directed contraction of collagenous gels in vitro depends on free access to a collagen site known to bind several extracellular matrix (ECM) proteins that form substrates for α β -directed cell attachment, such as fibronectin and fibrin. A streptococcal collagen-binding protein, CNE, specifically binds to and blocks this site on the collagen triple helix. Here we show that whereas CNE perturbed α β -directed and platelet-derived growth factor BB-induced normalization of dermal P after C48/80, it did not affect α β -dependent maintenance of a homeostatic dermal P . These data imply that dynamic modification of the ECM structure is needed during acute patho-physiological modulations of P but not for long-term maintenance of a homeostatic P . Our data thus show that collagen-binding β -integrins, integrin α β and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis.