Lung matrix incorporation of plasma fibronectin reduces vascular permeability in postsurgical bacteremia

Abstract

Plasma fibronectin (pFN) can incorporate into the lung extracellular matrix (ECM) as well as enhance hepatic cell phagocytic removal of bloodborne microparticulate debris that can contribute to lung vascular injury. Treatment of human pFN (hFN) with N-ethylmaleimide (NEM) blocks its ECM incorporation but not its ability to augment phagocytosis. Using hFN purified from fresh human plasma cryoprecipitate, we compared the effect of NEM-treated hFN versus normal hFN on lung transvascular protein clearance (TVPC) in postoperative bacteremic sheep to determine whether the ability of hFN to attenuate the increase in lung endothelial permeability required its ECM incorporation. Sheep with lung lymph fistulas were infused with a sublethal dose of Pseudomonas aeruginosa (5 x 10(8)) 48 h after surgery. In the first study, sheep received either FN-rich human cryoprecipitate, FN-deficient cryoprecipitate, FN purified from cryoprecipitate (hFN), FN-deficient cryoprecipitate reconstituted with purified hFN, or the sterile saline diluent. In the second study, sheep received either 200 mg of purified hFN (group I), 200 mg of NEM-treated hFN (group II), or the saline diluent (group III). In the first study, the increase in TVPC after bacterial challenge was attenuated by FN-rich cryoprecipitate, hFN, or reconstituted FN-deficient cryoprecipitate (P < 0.05) but not by saline and FN-deficient cryoprecipitate. In the second study, TVPC increased by 2 h (P < 0.05) and peaked over 4-8 h (P < 0.05) at 380-420% above baseline in postoperative bacteremic sheep given the diluent (group III). In contrast, intravenous infusion of hFN, but not of NEM-treated hFN, significantly (P < 0.05) attenuated this increase of lung protein clearance. Thus the ability for the intravenously infused purified pFN to attenuate the increase in lung endothelial protein permeability in sheep during postsurgical bacteremia appears to require its ECM incorporation into the interstitial ECM of the lung.

Opposite effects of tumor necrosis factor and soluble fibronectin on junctional adhesion molecule-A in endothelial cells

“…In addition, fibronectin ability to counteract TNF-induced permeability requires binding of fibronectin to the subendothelial matrix (43). Hence, fibronectin might attenuate TNF's effect by facilitating adhesion of endothelial cells to the matrix (32).…”

Radiation-induced toxicity in cancer patients with low plasma fibronectin levels

“…32 Here, we showed that plasma Fn levels are increased in lung cancer patients (Figure 1). In addition, the gradient between plasma and tissue Fn must be considered when alterations in plasma Fn levels are analysed.…”

“…In addition, the gradient between plasma and tissue Fn must be considered when alterations in plasma Fn levels are analysed. 32 Here, we showed that plasma Fn levels are increased in lung cancer patients (Figure 1). The anti-tumour response of the monocyteÀ macrophage system with an increase in Fn synthesis and turnover could be a viable explanation for these changes.…”

“…The plasma Fn levels during RT seem likely to reflect the balance between production of Fn from activated macrophage, endothelial cells, tumour cells and other cells and the consumption of Fn in reticuloendothelial system functions and tissue repair. In addition, the gradient between plasma and tissue Fn must be considered when alterations in plasma Fn levels are analysed 32 . Here, we showed that plasma Fn levels are increased in lung cancer patients (Figure 1).…”

“…The Fn levels in plasma and other body fluids have been reported to change in various disease states, including cancer, 19– 28 and may predict the toxic effect of therapeutic agents such as immunotoxins and IL-2 29 . The importance of cellular Fn in radiation pneumonitis and fibrosis has been emphasised in several series 30– 32 . It has been shown that bronchoalveolar lavage fluid levels of Fn, TGF-β1 and IL-6 are increased in patients with radiation pneumonitis 30, 31 .…”