Flick Matthew J, Du Xinli, Degen Jay L
Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
Exp Biol Med (Maywood). 2004 Dec;229(11):1105-10. doi: 10.1177/153537020422901104.
In addition to its well-characterized role in hemostasis, fibrin(ogen) has been proposed to be a central regulator of the inflammatory response. Multiple in vitro studies have demonstrated that this hemostatic factor can alter leukocyte function, including cell adhesion, migration, cytokine and chemokine expression, degranulation, and other specialized processes. One important link between fibrin(ogen) and leukocyte biology appears to be the integrin receptor alpha(M)beta(2)/Mac-1, which binds to immobilized fibrin(ogen) and regulates leukocyte activities. Although it is well established that fibrin(ogen) is a ligand for alpha(M)beta(2), the precise molecular determinants that govern this interaction are only now becoming clear. A novel line of mice expressing a mutant form of fibrinogen (Fib gamma(390-396A)) has revealed that gamma chain residues 390-396 are important for the high-affinity engagement of fibrinogen by alpha(M)beta(2) and leukocyte function in vivo. Fibrinogen gamma(390-396A) failed to support alpha(M)beta(2)-mediated adhesion of primary neutrophils, monocytes, and macrophages, and mice expressing this fibrinogen variant were found to exhibit a major defect in the host inflammatory response following acute challenges. Most notably, Fib gamma(390-396A) mice display a profound impediment in Staphylococcus aureus elimination by leukocytes following intraperitoneal inoculation. These findings have positively established the physiological importance of fibrin(ogen) as a ligand for alpha(M)beta(2) and illustrate that the fibrin(ogen) gamma chain residues 390-396 constitute a critical feature of the alpha(M)beta(2) binding motif. Finally, the Fib gamma(390-396A) mice represent a valuable system for better defining the contribution of fibrin(ogen) to the inflammatory response in the absence of any confounding alteration in clotting function.
除了在止血过程中已被充分描述的作用外，纤维蛋白（原）还被认为是炎症反应的核心调节因子。多项体外研究表明，这种止血因子可改变白细胞功能，包括细胞黏附、迁移、细胞因子和趋化因子表达、脱颗粒以及其他特殊过程。纤维蛋白（原）与白细胞生物学之间的一个重要联系似乎是整合素受体α(M)β(2)/Mac-1，它与固定化的纤维蛋白（原）结合并调节白细胞活性。尽管纤维蛋白（原）是α(M)β(2)的配体这一点已得到充分证实，但控制这种相互作用的精确分子决定因素现在才逐渐清晰。一种表达纤维蛋白原突变形式（Fibγ(390 - 396A)）的新型小鼠品系表明，γ链残基390 - 396对于α(M)β(2)与纤维蛋白原的高亲和力结合以及体内白细胞功能很重要。纤维蛋白原γ(390 - 396A)无法支持原代中性粒细胞、单核细胞和巨噬细胞的α(M)β(2)介导的黏附，并且发现表达这种纤维蛋白原变体的小鼠在急性刺激后的宿主炎症反应中表现出主要缺陷。最值得注意的是，Fibγ(390 - 396A)小鼠在腹腔接种后白细胞清除金黄色葡萄球菌方面表现出严重障碍。这些发现明确确立了纤维蛋白（原）作为α(M)β(2)配体的生理重要性，并表明纤维蛋白（原）γ链残基390 - 396构成了α(M)β(2)结合基序的关键特征。最后，Fibγ(390 - 396A)小鼠代表了一个有价值的系统，可用于在凝血功能无任何混淆性改变的情况下更好地确定纤维蛋白（原）对炎症反应的贡献。
