Department of Population Medicine, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
Elanco Canada Limited, Guelph, Ontario, Canada.
PLoS One. 2018 Jun 28;13(6):e0198701. doi: 10.1371/journal.pone.0198701. eCollection 2018.
Previous research in various species has shown that granulocyte-colony stimulating factor stimulates the production and release of neutrophils from bone marrow. The objective of this study was to characterize the effects of polyethylene glycol-bound bovine granulocyte colony-stimulating factor (pegbovigrastim; Imrestor, Elanco) on circulating leukocyte counts. Thirty-four Holstein cows were randomly assigned to receive 2 injections of either physiologic saline (n = 16) or pegbovigrastim (n = 18), 7 days before expected calving (d -7) and within 24 hours after calving (d 0). Cows were sampled at d -7, d -6, d 0, d +1, d +7, and d +21, relative to calving. Only cows for which the interval from the first injection to calving was ≥ 4 d and ≤ 10 d were included, such that the interval (mean ± SD) from first treatment to calving was 6.7 ± 1.9 d. Treatment effects were assessed with mixed linear regression models. After the first injection, neutrophil counts (×109/ L) in pegbovigrastim-treated cows increased from 4.3 (95% CI 3.8 to 4.8) at d -7 to 18.2 (CI 16.3 to 20.3) at d -6 (P < 0.0001). Their counts then decreased from d -6 to d 0, when the second injection was administered, at a rate of -0.31 ×109 neutrophils/L/day (P < 0.0001). After the second injection, neutrophil counts increased from 16.4 (CI 13.7 to 19.6) at d 0 to 32.8 (CI 25.2 to 42.7) at d +1 (P < 0.0001), after which counts decreased at a rate of -3.73 ×109 neutrophils/L/day until d +7 (P < 0.0001). Counts continued to decrease from d +7 to d +21 at a slower rate of -0.43 ×109 neutrophils/L/day (P < 0.0001), until baseline levels were reached. Conversely, in control cows, neutrophil counts were unchanged from d -7 to d -6 (P = 0.86) after the first injection and then decreased from 6.1 (CI 5.0-7.3) at d 0, to 3.2 (CI 2.4-4.2) at d +1 (P < 0.0001) after the second injection. Neutrophil count was greater (P < 0.001) in pegbovigrastim-treated than in control cows at days -6, 0, +1 and +7. Area under the curve (cells ×109/ L per 28 d) for neutrophil counts in the pegbovigrastim group was 429, versus 99 in the control group (P < 0.0001). The response to each injection of pegbovigrastim was additive and consisted of 95% segmented neutrophils, suggesting that the effect of the treatment was to release mature neutrophils from a substantial pool available in the bone marrow. The sustained increase in circulating neutrophil count around the time of calving may contribute to improved health during the peripartum transition period.
先前在各种物种中的研究表明，粒细胞集落刺激因子可刺激骨髓中中性粒细胞的产生和释放。本研究的目的是描述聚乙二醇结合牛粒细胞集落刺激因子（pegbo-vigrastim；Imrestor，Elanco）对循环白细胞计数的影响。34 头荷斯坦奶牛随机分为两组，每组 16 头，分别在预计分娩前 7 天（d-7）和分娩后 24 小时内（d0）接受 2 次生理盐水（n=16）或 pegbo-vigrastim（n=18）注射。从 d-7 到 d-6、d0、d+1、d+7 和 d+21，在分娩前后对奶牛进行采样。仅纳入从第一次注射到分娩的间隔时间≥4d 且≤10d 的奶牛，这样从第一次治疗到分娩的间隔时间为 6.7±1.9d。使用混合线性回归模型评估治疗效果。在第一次注射后，pegbo-vigrastim 治疗组的中性粒细胞计数（×109/L）从 d-7 的 4.3（95%CI 3.8 至 4.8）增加到 d-6 的 18.2（CI 16.3 至 20.3）（P＜0.0001）。然后，从 d-6 到 d0（第二次注射时），中性粒细胞计数以每天-0.31×109 个中性粒细胞/L 的速度下降（P＜0.0001）。第二次注射后，中性粒细胞计数从 d0 的 16.4（CI 13.7 至 19.6）增加到 d+1 的 32.8（CI 25.2 至 42.7）（P＜0.0001），之后计数以每天-3.73×109 个中性粒细胞/L 的速度下降，直到 d+7（P＜0.0001）。从 d+7 到 d+21，计数以较慢的速度（每天-0.43×109 个中性粒细胞/L）下降（P＜0.0001），直到达到基线水平。相反，在对照组奶牛中，第一次注射后，中性粒细胞计数从 d-7 到 d-6 没有变化（P=0.86），然后从 d0 的 6.1（CI 5.0 至 7.3）下降到 d+1 的 3.2（CI 2.4 至 4.2）（P＜0.0001）。pegbo-vigrastim 治疗组的中性粒细胞计数在 d-6、0、+1 和+7 时均高于对照组（P＜0.001）。pegbo-vigrastim 组的中性粒细胞计数曲线下面积（每 28d 细胞×109/L）为 429，而对照组为 99（P＜0.0001）。pegbo-vigrastim 的每次注射反应都是累加的，由 95%的成熟中性粒细胞组成，这表明该治疗的作用是从骨髓中大量可用的储备中释放成熟的中性粒细胞。分娩前后循环中性粒细胞计数的持续增加可能有助于改善围产期过渡期的健康状况。
