Hodge Sandra, Hodge Greg, Holmes Mark, Jersmann Hubertus, Reynolds Paul N
Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
Respirology. 2015 Jan;20(1):95-100. doi: 10.1111/resp.12415. Epub 2014 Oct 12.
Corticosteroid resistance in chronic obstructive pulmonary disease (COPD) is a major challenge. We have reported increased bronchial epithelial cell apoptosis and increased airway CD8 T-cell numbers in COPD. Apoptosis can be induced via the serine protease, granzyme B. However, glucocorticosteroids fail to adequately suppress granzyme B production by CD8 T cells. We previously showed that low-dose azithromycin reduced airways inflammation in COPD subjects and we hypothesized that it would also reduce granzyme B production by CD8 T cells.
We administered 250 mg azithromycin daily for 5 days then twice weekly (total 12 weeks) to 11 COPD subjects (five current smokers; six ex-smokers) and assessed granzyme B in the airway (bronchoalveolar lavage), intra-epithelial compartment and peripheral blood, collected before and following administration of azithromycin. To then dissect the effects of on CD4 and CD8 T-cell subsets, we applied an in vitro assay and physiologically relevant concentrations of azithromycin (and, for comparison, n-acetyl cysteine) and stimulation of peripheral blood mononuclear cells from five healthy subjects with CD3/CD28 T-cell expander.
T-cell granzyme B production in both airway and intra-epithelial compartments was reduced in COPD patients following 12 weeks of azithromycin treatment, with no significant effect in blood. Both azithromycin and n-acetyl cysteine suppressed CD4 T-cell granzyme B production, but only azithromycin was effective at reducing CD8+ T-cell granzyme B production in vitro.
We provide further evidence for the application of low-dose azithromycin as an attractive adjunct treatment option for controlling epithelial cell apoptosis, abnormal airway repair and chronic inflammation in COPD.
慢性阻塞性肺疾病（COPD）中的糖皮质激素抵抗是一项重大挑战。我们曾报道过COPD患者支气管上皮细胞凋亡增加以及气道CD8 T细胞数量增多。凋亡可通过丝氨酸蛋白酶颗粒酶B诱导产生。然而，糖皮质激素无法充分抑制CD8 T细胞产生颗粒酶B。我们之前发现低剂量阿奇霉素可减轻COPD患者的气道炎症，因此推测其也能减少CD8 T细胞产生颗粒酶B。
我们给予11例COPD患者（5例现吸烟者；6例既往吸烟者）每日250mg阿奇霉素，连用5天，之后每周两次（共12周），并在阿奇霉素给药前后采集气道（支气管肺泡灌洗）、上皮内区室及外周血样本，评估其中的颗粒酶B。为进一步剖析其对CD4和CD8 T细胞亚群的影响，我们进行了一项体外试验，应用生理相关浓度的阿奇霉素（以及作为对照的N-乙酰半胱氨酸），并用CD3/CD28 T细胞扩增剂刺激5名健康受试者的外周血单个核细胞。
阿奇霉素治疗12周后，COPD患者气道和上皮内区室的T细胞颗粒酶B产生均减少，而外周血中无显著变化。阿奇霉素和N-乙酰半胱氨酸均能抑制CD4 T细胞颗粒酶B的产生，但体外试验中只有阿奇霉素能有效降低CD8 + T细胞颗粒酶B的产生。
我们为低剂量阿奇霉素作为控制COPD上皮细胞凋亡、异常气道修复及慢性炎症的有吸引力的辅助治疗选择提供了进一步证据。
