查看Ch45 Hematopoietic Agents: Growth Factors, Minerals, and Vitamins的源代码

本页英文内容取自：药理学蓝皮圣经第 14 版 (Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 14th Edition, published in 2022)

中文内容由 BH1RBH (Jack Tan) 粗糙翻译

蓝色 <b style=color:#0cf>【注】</b> 后内容为 BH1RBH (Jack Tan) 所加之注释，便于理解记忆，内容大部来自于《药理学》人卫第十版

== Hematopoiesis ==

The finite life span of most mature blood cells requires their continuous replacement, a process termed hematopoiesis. New cell production must respond to basal needs and states of increased demand. Erythrocyte production can increase more than 20-fold in response to anemia or hypoxemia, leukocyte production increases dramatically in response to systemic infections, and platelet production can increase 10- to 20-fold when platelet consumption results in thrombocytopenia.

大多数成熟血细胞寿命有限需要不断更替，这一过程称为造血。新的细胞生产必须响应基本需求和增加要求的状态。红细胞的产生可因贫血或低氧血症而增加 20 倍以上，白细胞的产生可因全身感染而急剧增加，当血小板消耗导致血小板减少症时，血小板的产生可增加 10 至 20 倍。


The regulation of blood cell production is complex. Hematopoietic stem cells are rare marrow cells that manifest self-renewal and lineage commitment, resulting in cells destined to differentiate into the 10 or more distinct blood cell lineages. For the most part, this process occurs in the marrow cavities of the skull, vertebral bodies, pelvis, and proximal long bones; it involves interactions among hematopoietic stem and progenitor cells and the cells and complex macromolecules of the marrow stroma and is influenced by a number of soluble and membrane-bound hematopoietic growth factors. Several hormones and cytokines have been identified and cloned that affect hematopoiesis, permitting their production in quantities sufficient for research and, in some cases, therapeutic use. Clinical applications range from the treatment of primary hematological diseases (e.g., aplastic anemia, congenital neutropenia) to use as adjuncts in the treatment of severe infections and in the management of patients with kidney failure or those undergoing cancer chemotherapy or marrow transplantation.

血细胞生成的调节很复杂。造血干细胞是罕见的骨髓细胞，表现出自我更新和谱系承诺，导致细胞注定要分化成 10 个或更多不同的血细胞谱系。在大多数情况下，这个过程发生在颅骨的骨髓腔、椎体、骨盆和近端长骨中；它涉及造血干细胞和祖细胞与骨髓基质细胞和复杂大分子之间的相互作用，并受许多可溶性和膜结合造血生长因子的影响。已经鉴定并克隆了几种影响造血的激素和细胞因子，使其能够产生足够的数量用于研究，在某些情况下，还可用于治疗。临床应用范围从治疗原发性血液病（例如再生障碍性贫血、先天性中性粒细胞减少症）到用作严重感染治疗的辅助治疗以及肾衰竭患者或接受癌症化疗或骨髓移植的患者的管理。


Hematopoiesis also requires an adequate supply of minerals (e.g., iron, cobalt, and copper) and vitamins (e.g., folic acid, vitamin B12, pyridoxine, ascorbic acid, and riboflavin); deficiencies generally result in characteristic anemias or, less frequently, a general failure of hematopoiesis (Rojas-Hernandez and Oo, 2018). Therapeutic correction of a specific deficiency state depends on the accurate diagnosis of the basis for the anemia and on knowledge about the correct dose, formulation, and route of administration of the deficient mineral(s) or vitamin(s).

造血还需要充足的矿物质（例如铁、钴和铜）和维生素（例如叶酸、维生素 B12、吡哆醇、抗坏血酸和核黄素）；缺乏通常会导致特征性贫血，或者较少见的是造血功能普遍失效（Rojas-Hernandez 和 Oo，2018 年）。特定缺乏状态的治疗纠正取决于对贫血基础的准确诊断，以及对缺乏矿物质或维生素的正确剂量、配方和给药途径的了解。

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== Growth Factor Physiology ==

Steady-state hematopoiesis encompasses the tightly regulated production of more than 400 billion blood cells each day. The hematopoietic organ also is unique in adult physiology in that several mature cell types are derived from a much smaller number of multipotent progenitors, which develop from a more limited number of pluripotent hematopoietic stem cells. Such cells are capable of maintaining their own number and differentiating under the influence of cellular and humoral factors to produce the large and diverse number of mature blood cells.

稳态造血包括每天超过 4000 亿个血细胞的严格调节产生。造血器官在成人生理学中也是独一无二的，因为几种成熟的细胞类型来源于数量少得多的多能祖细胞，这些祖细胞是从数量更有限的多能造血干细胞发育而来的。这种细胞能够保持自身的数量并在细胞和体液因子的影响下分化，以产生大量多样的成熟血细胞。


Our understanding of stem cell differentiation owes much to the in vitro culture of marrow cells. Using the results from clonal cultures in semisolid medium, stem cell differentiation can be described as a series of developmental steps that produce mixed blood cell lineage colonies, which give rise to large, immature and small, mature single-lineage burstforming units (BFUs) and colony-forming units (CFUs), respectively, for each of the major blood cell types. These early progenitors (BFUs and CFUs) are capable of further proliferation and differentiation, increasing their number by some 30-fold. It is at this most mature stage of development that the lineage-committed growth factors (colony-stimulating factors [CSFs] for monocytes [M-CSFs] and granulocytes [G-CSFs], erythropoietin, and thrombopoietin) exert their primary proliferative and differentiative effects. Overall, proliferation and maturation of the CFU for each cell line can amplify the resulting mature cell product by another 30-fold or more, generating more than 1000 mature cells from each committed stem cell.

我们对干细胞分化的理解在很大程度上归功于骨髓细胞的体外培养。利用半固体培养基中克隆培养的结果，干细胞分化可以描述为产生混合血细胞谱系集落的一系列发育步骤，这些集落分别为每种主要血细胞类型产生大的、未成熟的和小的成熟单谱系爆发形成单位 （BFU） 和集落形成单位 （CFU）。这些早期祖细胞（BFU 和 CFU）能够进一步增殖和分化，使其数量增加约 30 倍。正是在这个最成熟的发育阶段，谱系定型生长因子（单核细胞 [M-CSF] 和粒细胞 [G-CSF] 的集落刺激因子 [CSF]、促红细胞生成素和血小板生成素）发挥其主要的增殖和分化作用。总体而言，每种细胞系的 CFU 增殖和成熟可以将所得成熟细胞产物再扩增 30 倍或更多，从每个定型干细胞中产生 1000 多个成熟细胞。


Hematopoietic and lymphopoietic growth factors are glycoproteins produced by a number of marrow cells and peripheral tissues. They are active at very low concentrations and typically affect more than one committed cell lineage. Most interact synergistically with other factors and stimulate production of additional growth factors, a process termed networking. Growth factors generally exert actions at several points in the processes of cell proliferation and differentiation and in mature cell function. However, the network of growth factors that contributes to any given cell lineage depends absolutely on a nonredundant, lineage-specific factor, such that absence of factors that stimulate developmentally early progenitors is compensated for by redundant cytokines, but loss of the lineage-specific factor leads to a specific cytopenia. Some of the overlapping and nonredundant effects of the more important hematopoietic growth factors are illustrated in Figure 45–1 and Table 45–1.

造血和淋巴细胞生长因子是由许多骨髓细胞和外周组织产生的糖蛋白。它们在非常低的浓度下具有活性，通常影响多个定型细胞系。大多数与其他因子协同作用并刺激其他生长因子的产生，这一过程称为网络。生长因子通常在细胞增殖和分化过程以及成熟细胞功能的多个时间点发挥作用。然而，有助于任何给定细胞谱系的生长因子网络绝对取决于非冗余的谱系特异性因子，因此刺激发育早期祖细胞因子的缺失被冗余的细胞因子补偿，但谱系特异性因子的缺失会导致特异性血细胞减少症。图 45-1 和表 45-1 说明了更重要的造血生长因子的一些重叠和非冗余效应。

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== Erythropoiesis-Stimulating Agents ==

Erythropoiesis-stimulating agent (ESA) is the term given to a pharmacological substance that stimulates red blood cell production.

红细胞生成刺激剂 （ESA） 是指刺激红细胞生成的药理学物质。

=== Erythropoietin (EPO) ===
促红细胞生成素

Erythropoietin is the most important regulator of the proliferation of committed erythroid progenitors (CFU-E, colony forming units, erythrocyte) and their immediate progeny. In its absence, severe anemia is invariably present, commonly seen in patients with renal failure. Erythropoiesis is controlled by a feedback system in which a sensor in the kidney detects changes in oxygen delivery to modulate the erythropoietin secretion. The sensor mechanism is now understood at the molecular level (Haase, 2010).

促红细胞生成素是定型红细胞祖细胞 （CFU-E，集落形成单位，红细胞） 及其直接后代增殖的最重要调节因子。在没有肾功能衰竭的情况下，总是会出现严重贫血，常见于肾功能衰竭患者。红细胞生成由反馈系统控制，其中肾脏中的传感器检测氧气输送的变化以调节促红细胞生成素的分泌。传感器机制现在可以在分子水平上理解 （Haase， 2010）。


Hypoxia-inducible factor (HIF), a heterodimeric (HIF-1α and HIF-1β) transcription factor, enhances expression of multiple hypoxia-inducible genes, such as vascular endothelial growth factor and erythropoietin. HIF-1α is labile due to its prolyl hydroxylation and subsequent polyubiquitination and degradation, aided by the von Hippel-Lindau (VHL) protein. During states of hypoxia, the prolyl hydroxylase is inactive, allowing the accumulation of HIF-1α and activating erythropoietin expression, which in turn stimulates rapid expansion of erythroid progenitors. Specific alteration of VHL leads to an oxygen-sensing defect, characterized by constitutively elevated levels of HIF-1α and erythropoietin, with resultant polycythemia (Gordeuk et al., 2004). A second isoform of HIF, HIF-2α, is an important regulator of the expression of genes that contribute to iron absorption (Mastrogiannaki et al., 2013); a genetic gain-of-function mutation in HIF-2α also induces erythrocytosis in patients (Percy et al., 2008).

缺氧诱导因子 （HIF） 是一种异二聚体 （HIF-1α 和 HIF-1β） 转录因子，可增强多个缺氧诱导基因的表达，例如血管内皮生长因子和促红细胞生成素。HIF-1α 不稳定，因为它的脯氨酰羟基化和随后的多泛素化和降解，在 von Hippel-Lindau （VHL） 蛋白的帮助下。在缺氧状态下，脯氨酰羟化酶失活，允许 HIF-1α 积累并激活促红细胞生成素表达，进而刺激红细胞祖细胞的快速扩增。VHL 的特异性改变导致氧感应缺陷，其特征是 HIF-1α 和促红细胞生成素水平组成性升高，从而导致红细胞增多症（Gordeuk 等人，2004 年）。HIF 的第二种亚型 HIF-2α 是有助于铁吸收的基因表达的重要调节因子（Mastrogiannaki等人，2013 年）；HIF-2α 中的遗传功能获得性突变也会诱导患者的红细胞增多症 （Percy et al.， 2008）。


Erythropoietin is expressed primarily in peritubular interstitial cells of the kidney. Erythropoietin contains 193 amino acids, of which the first 27 are cleaved during secretion. The final hormone is heavily glycosylated and has a molecular mass of about 30 kDa. After secretion, erythropoietin binds to a receptor on the surface of committed erythroid progenitors in the marrow and is internalized. With anemia or hypoxemia, synthesis rapidly increases by 100-fold or more, serum erythropoietin levels rise, and marrow progenitor cell survival, proliferation, and maturation are dramatically stimulated. This finely tuned feedback loop can be disrupted by kidney disease, marrow damage, or a deficiency in iron or an essential vitamin. With an infection or an inflammatory state, erythropoietin secretion, iron delivery, and progenitor proliferation all are suppressed by inflammatory cytokines, but this accounts for only part of the resultant anemia; interference with iron metabolism also is a result of inflammatory mediator actions on the hepatic protein hepcidin (Drakesmith and Prentice, 2012). Loss of hepcidin-producing liver mass or genetic or acquired conditions that repress hepcidin production by the liver may lead to iron overload (Pietrangelo, 2016).

促红细胞生成素主要在肾脏的肾小管周围间质细胞中表达。促红细胞生成素含有 193 个氨基酸，其中前 27 个氨基酸在分泌过程中被裂解。最终激素是高度糖基化的，分子量约为 30 kDa。分泌后，促红细胞生成素与骨髓中定型红细胞祖细胞表面的受体结合并被内化。贫血或低氧血症时，合成迅速增加 100 倍或更多，血清促红细胞生成素水平升高，骨髓祖细胞存活、增殖和成熟受到显著刺激。这种微调的反馈回路可能会因肾脏疾病、骨髓损伤或铁或必需维生素缺乏而中断。在<b style=color:#0cf>感染或炎症</b>状态下，<b style=color:#f80>促红细胞生成素</b>分泌、<b style=color:#f80>铁</b>递送和<b style=color:#f80>祖细胞</b>增殖<b style=color:#0b0>都受炎性细胞因子的抑制</b>，但这只是导致贫血的一部分；对铁代谢的干扰也是炎症介质对肝蛋白铁调素作用的结果（Drakesmith 和 Prentice，2012 年）。产生铁调素的肝脏质量的损失或抑制肝脏产生铁调素的遗传或获得性疾病可能导致铁过载（Pietrangelo，2016 年）。

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=== Sequestration of Transforming Growth Factor β Superfamily Ligands ===
转化生长因子β超家族配体的隔离

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== Myeloid Growth Factors ==
髓系生长因子

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== Thrombopoietic Growth Factors ==
血小板生成生长因子

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== Iron Deficiency and Other Hypochromic Anemias ==
缺铁和其他低色素性贫血

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== Vitamin B12, Folic Acid, and the Treatment of Megaloblastic Anemias ==
维生素 B12、叶酸和巨幼红细胞性贫血的治疗

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== Folic Acid and Human Health ==
叶酸与人类健康

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== Reference ==

* [[Pharmacology]]
* [[Physiology]]
* [[Addiction]]
* [[BBB]] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080800/ 血脑屏障概述]

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