| The role of fibroblasts and platelets, not traditionally considered as immune cells, in wound healing, inflammation, and transfusion reactions was investigated. Lung fibrosis results from dysregulated wound healing and is hallmarked by foci of hyperproliferating fibroblasts. Disruption of the CD40--CD154 (CD40 ligand) pathway is known to reduce lung inflammation and fibrosis. We sought to identify the source of CD 154 in the lung.{09}We found that: (1) primary strains of human lung fibroblasts are a novel source of CD 154, (2) fibroblasts generated from fibrotic regions of the lung express higher levels of CD154 than their non-fibrotic counterparts, (3) CD 154 expression is downregulated by IFNgamma, an antifibrotic Th1 cytokine, and enhanced by IL-13, a profibrotic Th2 cytokine and (4) high levels of in situ CD154 were observed in fibrotic lung tissues as compared to controls. These data support the idea of fibroblasts as non-traditional immune cells due to their expression of CD154.; Another potential source of CD154 in the lung is the platelets. Activated platelets express CD 154 on their membranes as well as expel it. We show that platelet derived CD154 can activate CD40 positive fibroblasts to produce the proinflammatory mediators COX-2, PGE2, IL-6 and IL-8. We also demonstrate, for the first time, that thromboxane A2 (TXA2), a major prostanoid product of platelets, is a potent fibroblast activator, causing the induction of COX-2, IL-6 and IL-8. In the context of tissue injury, platelet/plasma derived TXA2 and CD154 link together thrombosis, inflammation and wound healing.; We also investigated the role of platelet CD154 in platelet transfusion reactions. Herein, we demonstrate that platelets prepared for transfusion "spontaneously" express surface CD154 and release CD154 into the plasma during storage. Interestingly, we found that the kinetics of sCD154 release were such that maximum levels were already achieved by the time patients received transfusions. We demonstrate that sCD154 in platelet concentrates is biologically active via its ability to stimulate lung fibroblasts to produce proinflammatory mediators. We propose that transfusion of platelet concentrates is accompanied by the infusion of large amounts of membrane and soluble CD154 and that this may be the underlying cause of platelet transfusion reactions. |
