Tilmicosin is widely used to treat respiratory infections in animals and has been reported to induce cardiac damage and even sudden death. However, its exact mechanisms, especially in chickens, remain unclear. This study confirmed the dose-dependent damaging effect of tilmicosin on primary chicken myocardial cells. Primary chicken myocardial cells treated with tilmicosin (0.5 μg/mL) for 0 h, 12 h, and 48 h were subjected to RNA sequencing and bioinformatics analysis. Transcriptomic analysis revealed that cytokine-cytokine receptor interactions, calcium signaling pathway, peroxisomes, phagosomes, mitogen-activated protein kinase (MAPK) signaling pathway, and oxidative phosphorylation were significantly and differentially affected after 12 h or 48 h of tilmicosin treatment. Further evidence demonstrated consistently increased proinflammatory factors, peroxidation, and ferroptosis, and intracellular ion imbalance was caused by tilmicosin for 12 h, but this imbalance had recovered at 48 h. Meanwhile, intracellular resistance to tilmicosin-induced toxicity involved the active regulation of cyclooxygenase-1 and ATPase H+/K+-transporting beta subunit at 48 h, sustained activation of MAPK12, and downregulation of dual specificity phosphatase 10 at 12 h. In summary, this study suggests that tilmicosin exerts its cardiotoxicity in primary chicken myocardial cells through multiple mechanisms and finds several intracellular molecular targets to resist the toxicity.

中文翻译：

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转录组学研究表明，在鸡原代心肌细胞中，由替米考星引起的毒性破坏和对替米考星的潜在耐药性。

替米考星被广泛用于治疗动物的呼吸道感染，据报道可引起心脏损害，甚至猝死。但是，其确切机制，特别是在鸡中，仍不清楚。这项研究证实了替米考星对鸡原代心肌细胞的剂量依赖性破坏作用。用替米考星（0.5μg/ mL）处理0 h，12 h和48 h的原代鸡心肌细胞进行RNA测序和生物信息学分析。转录组学分析显示，在替米考星处理12 h或48 h后，细胞因子与细胞因子受体的相互作用，钙信号传导途径，过氧化物酶体，吞噬体，促分裂原活化蛋白激酶（MAPK）信号传导途径和氧化磷酸化受到显着和差异性的影响。进一步的证据表明，促炎因子持续增加，替米考星持续12 h引起过氧化，铁变性和细胞内离子失衡，但这种失衡在48 h时已恢复。同时，细胞内对替米考星诱导的毒性的抗性涉及在48 h时主动调节环氧合酶-1和ATPase H + / K +转运β亚基，持续激活MAPK12，并在12 h下调双重特异性磷酸酶10。总而言之，这项研究表明，替米考星通过多种机制在原代鸡心肌细胞中发挥其心脏毒性作用，并发现了几种可抵抗这种毒性的细胞内分子靶标。在细胞内对替米考星诱导的毒性的抗性涉及在48 h时主动调节环氧合酶-1和ATPase H + / K +转运β亚基，持续激活MAPK12，并在12 h下调双重特异性磷酸酶10。总而言之，这项研究表明，替米考星通过多种机制在原代鸡心肌细胞中发挥其心脏毒性作用，并发现了几种可抵抗这种毒性的细胞内分子靶标。在细胞内对替米考星诱导的毒性的抗性涉及在48 h时主动调节环氧合酶-1和ATPase H + / K +转运β亚基，持续激活MAPK12，并在12 h下调双重特异性磷酸酶10。总而言之，这项研究表明，替米考星通过多种机制在原代鸡心肌细胞中发挥其心脏毒性作用，并发现了几种可抵抗这种毒性的细胞内分子靶标。