Mild and moderate chronic hypercapnia elicit distinct transcriptomic responses of immune function in cardiorespiratory nuclei.
Mild and moderate chronic hypercapnia elicit distinct transcriptomic responses of immune function in cardiorespiratory nuclei.
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轻度和中度慢性高碳酸血症会引起心肺核中免疫功能的独特转录组反应。
DOI：
10.1152/physiolgenomics.00038.2023
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发表时间：
2023
影响因子：
4.6
通讯作者：
Forster,HubertV
中科院分区：
文献类型：
--
作者：
Grams,KirstynJ;Neumueller,SuzanneE;MouradianJr,GaryC;Burgraff,NicholasJ;Hodges,MatthewR;Pan,Lawrence;Forster,HubertV
慢性高碳酸血症（CH）是呼吸系统相关疾病的标志，高碳酸血症水平可急性或渐进式变得更加严重。在此之前，我们已经证明了成年山羊在轻度（动脉Pco2 ~ 55 mmHg）和中度（~ 60 mmHg） CH期间稳态生理学的时间依赖性适应，包括短暂的（轻度）或持续的（中度）急性化学敏感性抑制，这表明随着CH水平的增加，适应性呼吸控制机制存在局限性。在心肺控制关键节点中，谷氨酸受体可塑性、白细胞介素-1 β和血清素能调节的特定标记物的变化并不能完全解释对CH的生理适应。在这里，我们使用了一种无偏倚的方法（大组织RNA测序）来检验轻度或中度CH在心肺控制的重要脑干区域中引起不同基因表达谱的假设。这可能解释了大脑区域对CH基因表达谱的不同反应，验证了组织活检方法的准确性。差异基因表达分析显示，与内侧前额叶皮层相比，CH对脑干部位的影响更大。轻度CH引起主要免疫相关基因的上调，并预测免疫相关途径和功能的激活。相比之下，中度CH广泛导致基因下调，并预测与免疫反应和血管功能相关的细胞通路失活。这些数据表明，轻度CH会导致脑干内神经炎症通路的稳态激活，而中度CH则会导致相反的反应。免疫相关功能的转录变化可能是心肺网络在CH逐渐升高时对急性、更严重的高碳酸血症做出反应的能力的基础。轻度慢性高碳酸血症（CH）广泛上调免疫相关基因，并预测与免疫细胞活性和整体免疫反应相关的生物途径的激活。相比之下，中度CH主要下调与主要组织相容性复合体信号和血管功能相关的基因，导致涉及免疫反应和血管内皮功能的途径失活。免疫反应的严重依赖效应表明，神经炎症在CH中起重要作用，可能在维持急性和慢性高碳酸血症的适当通气反应中起重要作用。
Chronic hypercapnia (CH) is a hallmark of respiratory-related diseases, and the level of hypercapnia can acutely or progressively become more severe. Previously, we have shown time-dependent adaptations in steady-state physiology during mild (arterial Pco2∼55 mmHg) and moderate (∼60 mmHg) CH in adult goats, including transient (mild CH) or sustained (moderate CH) suppression of acute chemosensitivity suggesting limitations in adaptive respiratory control mechanisms as the level of CH increases. Changes in specific markers of glutamate receptor plasticity, interleukin-1ß, and serotonergic modulation within key nodes of cardiorespiratory control do not fully account for the physiological adaptations to CH. Here, we used an unbiased approach (bulk tissue RNA sequencing) to test the hypothesis that mild or moderate CH elicits distinct gene expression profiles in important brain stem regions of cardiorespiratory control, which may explain the contrasting responses to CH. Gene expression profiles from the brain regions validated the accuracy of tissue biopsy methodology. Differential gene expression analyses revealed greater effects of CH on brain stem sites compared with the medial prefrontal cortex. Mild CH elicited an upregulation of predominantly immune-related genes and predicted activation of immune-related pathways and functions. In contrast, moderate CH broadly led to downregulation of genes and predicted inactivation of cellular pathways related to the immune response and vascular function. These data suggest that mild CH leads to a steady-state activation of neuroinflammatory pathways within the brain stem, whereas moderate CH drives the opposite response. Transcriptional shifts in immune-related functions may underlie the cardiorespiratory network’s capability to respond to acute, more severe hypercapnia when in a state of progressively increased CH.NEW & NOTEWORTHYMild chronic hypercapnia (CH) broadly upregulated immune-related genes and a predicted activation of biological pathways related to immune cell activity and the overall immune response. In contrast, moderate CH primarily downregulated genes related to major histocompatibility complex signaling and vasculature function that led to a predicted inactivation of pathways involving the immune response and vascular endothelial function. The severity-dependent effect on immune responses suggests that neuroinflammation has an important role in CH and may be important in the maintenance of proper ventilatory responses to acute and chronic hypercapnia.