Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation.

C57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1).

Pulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days.

The striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.

结节病是一种原因不明的慢性炎症性疾病，其特征是肉芽肿形成。肉芽肿的慢性持久性机制尚不清楚。基质金属蛋白酶12（MMP12）降解细胞外基质弹性蛋白，并使免疫细胞浸润，引起炎症和肉芽肿形成。先前的研究报道结节病患者中MMP12的增加以及MMP12表达与疾病严重程度之间的关联。我们还在肉芽肿性炎症的多壁碳纳米管（MWCNT）小鼠模型中观察到MMP12升高。在这里我们假设MMP12对肉芽肿​​发病的急性和晚期很重要。为了验证这一假设，我们分析了肉芽肿和炎症反应MMP12淘汰赛 滴注MWCNT后10天（急性）和60天（晚期）的（KO）小鼠。

C57BL / 6（野生型）和 mp12KO小鼠经口咽滴注MWCNT。滴注后第3、10、20和60天收集肺，以评估MMP12表达和肉芽肿改变。在MWCNT滴注60天后分析了支气管肺泡灌洗（BAL）细胞的表达，认为其在结节性肉芽肿中起作用：过氧化物酶体增殖物激活受体-γ（PPARγ），干扰素-γ（IFN-γ）和CCL2（MCP -1）。

滴注MWCNT后10天的肺肉芽肿的出现与野生型和正常无差异。 mp12KO小鼠。相反，在MWCNT滴注后60天，mp12与野生型相比，KO小鼠显示BAL细胞中肉芽肿形成明显减弱，PPARγ升高，IFNγ表达降低。不料，mp12 KO小鼠进一步证实60天时肺泡巨噬细胞增加，CCL2增加。

第60天肉芽肿形成显着减少 mp12KO小鼠表明，MMP12是维持慢性肉芽肿病理生理所必需的。PPARγ增加和IFNγ减少的发现表明，这些介体也可能参与其中，因为先前的研究表明PPARγ抑制IFNγ，而PPARγ缺乏会加剧肉芽肿的形成。有趣的是，巨噬细胞流入和CCL2的增加也提示了MMP12在肉芽肿消退中的作用。总体而言，我们的结果强烈暗示MMP12是肉芽肿持续性的关键因素，并可能成为慢性肺结节病的可能治疗靶标。