Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2012;7(7):e41881. doi: 10.1371/journal.pone.0041881. Epub 2012 Jul 30.
Possession of a properly functioning innate immune system in the lung is vital to prevent infections due to the ongoing exposure of the lung to pathogens. While mechanisms of pulmonary innate immunity have been well studied, our knowledge of how these systems are altered in disease states, leading to increased susceptibility to infections, is limited. One innate immune protein in the lung, the pulmonary collectin SP-D, has been shown to be important in innate immune defense, as well as clearance of allergens and apoptotic cells. MMP-9 is a protease with a wide variety of substrates, and has been found to be dysregulated in a myriad of lung diseases ranging from asthma to cystic fibrosis; in many of these conditions, there are decreased levels of SP-D. Our results indicate that MMP-9 is able to cleave SP-D in vitro and this cleavage leads to loss of its innate immune functions, including its abilities to aggregate bacteria and increase phagocytosis by mouse alveolar macrophages. However, MMP-9-cleaved SP-D was still detected in a solid-phase E. coli LPS-binding assay, while NE-cleaved SP-D was not. In addition, MMP-9 seems to cleave SP-D much more efficiently than NE at physiological levels of calcium. Previous studies have shown that in several diseases, including cystic fibrosis and asthma, patients have increased expression of MMP-9 in the lungs as well as decreased levels of intact SP-D. As patients suffering from many of the diseases in which MMP-9 is over-expressed can be more susceptible to pulmonary infections, it is possible that MMP-9 cleavage of SP-D may contribute to this phenotype.
肺部拥有正常运作的固有免疫系统对于预防感染至关重要，因为肺部会持续接触病原体。虽然肺部固有免疫的机制已经得到了充分的研究，但我们对于这些系统在疾病状态下如何发生改变，从而导致对感染的易感性增加的了解是有限的。肺部的一种固有免疫蛋白，肺表面活性物质蛋白-D（SP-D），已被证明在固有免疫防御以及清除过敏原和凋亡细胞方面具有重要作用。基质金属蛋白酶-9（MMP-9）是一种具有广泛底物的蛋白酶，已在从哮喘到囊性纤维化等多种肺部疾病中发现其失调；在许多这些情况下，SP-D 的水平降低。我们的结果表明，MMP-9 能够在体外切割 SP-D，这种切割导致其丧失固有免疫功能，包括聚集细菌和增加肺泡巨噬细胞吞噬的能力。然而，在固相大肠杆菌脂多糖结合测定中仍然检测到 MMP-9 切割的 SP-D，而 NE 切割的 SP-D 则没有。此外，MMP-9 似乎比 NE 在生理钙水平下更有效地切割 SP-D。先前的研究表明，在包括囊性纤维化和哮喘在内的几种疾病中，患者肺部的 MMP-9 表达增加，而完整的 SP-D 水平降低。由于患有许多 MMP-9 过度表达的疾病的患者更容易发生肺部感染，因此 MMP-9 对 SP-D 的切割可能导致这种表型。
