PDF《Pulmonary Stromal-Derived Factor-1》

s onset and its progression (2C4). The neutrophilic response seen in ALI may be considered to occur in two phases: an initial recruitment of neu- trophils to the lung after an inciting injury and a second, persistent in?ux of these cells that further injures the already damaged lung (3, 5C8). Animal and human data suggest that this second or per- sistent phase of pulmonary neutrophilia represents the recruit- ment of marrow-released neutrophils that manifest a distinct phe- notype characterized by increased oxidant production and greater cell stiffness, size, and adherence but decreased chemotaxis and diapedesis to proin?ammatory cytokines (9C13). Such a cellular phenotype appears to re?ect functional immaturity due to acceler- ated marrow release (14C16), and has been implicated in the pathophysiology of ALI (13, 16, 17). Animal models and clinical studies have established that injuries inciting ALI result in a rapid induction of proin?ammatory cyto- kines that drive the initial recruitment of neutrophils to the lung (18). Although relevant human data are con?icting (3, 19C22), mouse models of ALI demonstrate that the neutrophil attractant cytokines (such as KC and MIP-2) rapidly taper in both the blood and the lung after initial release despite the ongoing recruitment of neutrophils to the lung (8, 19, 23C27). Thus, although the persis- tent recruitment of neutrophils in ALI may in part represent a residual effect of early cytokine release, the mechanisms underly- ing this critical later phase of the disease are unclear. In addition to the attenuation of neutrophil attractant cytokines in the persistent phase of ALI, characteristics of the neutrophilia itself suggest that different mechanisms may drive this process. Neutrophils in the persistent phase of in?ammation enter the circulation as a result of greatly accelerated marrow release and, as a consequence, possess a blunted chemoattractant response to traditional neutrophil che- mokines (9, 14). Thus, persistent neutrophilia may require not only an alteration in marrow neutrophil retention but alternative path- ways of neutrophil chemoattraction to, and diapedesis within, the lung. One potential chemokine pathway modulating persistent neutro- philia in ALI is the CXCR4/SDF-1 axis. First described in 1996, the CXC chemokine stromal-derived factor-1 (SDF-1) was ini- tially thought to be constitutively expressed in lymphoid organs and the bone marrow and to be critical for hemopoietic develop- ment and lymphocyte homing through its cognate receptor CXCR4 (28C30). Subsequently, it has been shown that SDF-1 is both more widely expressed and actively modulated (31). Recent reports have described the pulmonary expression of SDF-1 and have suggested roles for this cytokine in the homing of both malignant metastases and adult stem cells to the lung in mouse models (32C37). Al- though SDF-1 appears to be up-regulated in an animal model of *Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405;

and ? Department of Medicine and ? Department of Pathology, National Jewish Medical and Research Center, Denver, CO

80206 Received for publication May 16, 2006. Accepted for publication April 9, 2007. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with

18 U.S.C. Section

1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grants K08 HL04499 and 1R01 HL084200.

2 Address correspondence and reprint requests to Dr. Benjamin T. Suratt, University of Vermont College of Medicine,