Combat Wound Care, U.S. Army Institute of Surgical Research, JBSA-Fort Sam Houston, TX, 78234, USA.
BMC Musculoskelet Disord. 2022 Jul 27;23(1):716. doi: 10.1186/s12891-022-05667-1.
Delayed fracture healing caused by soft tissue loss can be resolved by the administration of a Th1 immunosuppressant, such as FK506. Additionally, open fractures are at high risk for infection. We hypothesized that the inclusion of an immunosuppressant to a subject at risk for a musculoskeletal infection will increase the likelihood of infection.
A rat model of musculoskeletal infection was used. Sprague Dawley rats received a stabilized femur defect and were inoculated with 10 CFU Staphylococcus aureus via a collagen matrix. Six hours after inoculation, the wounds were debrided of collagen and devitalized tissue and irrigated with sterile saline. The animals were randomized into two groups: carrier control and FK506, which were administered daily for 14 days and were euthanized and the tissues harvested to measure local bioburden.
The dosing regimen of FK506 that restored bone healing increased the bioburden in the bone and on the fixation implant compared to the carrier control animals. As expected, the administration of FK506 decreased circulating white blood cells, lymphocytes, neutrophils, and monocytes. Additionally, the red blood cell count, hematocrit, and body weight were lower in those animals that received FK506 compared to carrier control.
FK506 administration decreased the systemic immune cell counts and increased the bacterial bioburden within a model of musculoskeletal infection. Collectively, these outcomes could be attributed to the overall T cell suppression by FK506 and the altered antimicrobial activity of innate cells, thereby allowing S. aureus to thrive and subsequently leading to infection of severe, musculoskeletal injuries. These observations reveal the crucial continued investigation for the clinical use of FK506, and other immunosuppressant compounds, in trauma patients who are at increased risk of developing infections.
软组织缺失导致的骨折愈合延迟可以通过给予 Th1 免疫抑制剂来解决，如 FK506。此外，开放性骨折感染风险高。我们假设，在发生肌肉骨骼感染风险的患者中加入免疫抑制剂会增加感染的可能性。
使用肌肉骨骼感染大鼠模型。Sprague Dawley 大鼠接受稳定股骨缺损，并通过胶原蛋白基质接种 10 CFU 金黄色葡萄球菌。接种后 6 小时，切除胶原和失活组织的伤口，并使用无菌生理盐水冲洗。动物随机分为两组：载体对照组和 FK506 组，每天给药 14 天，然后安乐死并采集组织以测量局部生物负荷。
与载体对照组相比，恢复骨愈合的 FK506 给药方案增加了骨和固定植入物的生物负荷。如预期的那样，FK506 的给药降低了循环白细胞、淋巴细胞、中性粒细胞和单核细胞的数量。此外，与载体对照组相比，接受 FK506 的动物的红细胞计数、血细胞比容和体重较低。
FK506 给药降低了系统性免疫细胞计数，并增加了肌肉骨骼感染模型中细菌的生物负荷。总的来说，这些结果可能归因于 FK506 对 T 细胞的全面抑制以及固有细胞抗菌活性的改变，从而使金黄色葡萄球菌得以茁壮成长，并随后导致严重的肌肉骨骼感染。这些观察结果揭示了 FK506 和其他免疫抑制剂化合物在创伤患者中的临床应用需要进一步研究的重要性，这些患者发生感染的风险增加。
