氯离子通道在离体人肺泡上皮液体清除过程中的作用

目的探讨囊性纤维化跨膜传导调节体（CFTR）氯离子通道在离体人肺脏肺泡上皮液体清除过程中的作用以及β3-肾上腺素能受体激动剂BRL-37344对于人肺泡上皮液体清除能力的影响机制。方法采用离体人肺脏,以肺泡内液体白蛋白浓度的变化来测定人肺脏肺泡液体清除率（AFC）。结果BRL-37344可以提高AFC（P〈0.05）。选择性β3-肾上腺素能受体抑制剂SR-59230A、CFTR氯通道抑制剂CFTRinh-172圴可以部分抑制BRL-37344引起的AFC的提高（P〈0.05）。CFTR氯离子通道开放剂NS004可以提高AFC（P〈0.05）,钠离子通道抑制剂氨氯吡咪和CFTRinh-172可以完全抑制NS004提高AFC的作用（P〈0.001）。同时氨氯吡咪可以完全阻断BRL-37344提高AFC的作用。结论BRL-37344和NS004可以提高离体人肺脏AFC。BRL-37344对AFC的提高作用部分是通过CFTR氯离子通道调节的,CFTR氯通道的开放剂NS004对于AFC的调节作用可能是通过钠离子通道和氯离子通道共同完成的。     

肺泡内液体清除机制研究进展

肺水肿是临床常见疾病,肺泡液的吸收和消散对于减慢肺水肿的形成速度、改善肺水肿的预后至关重要。本文从上皮钠通道、水通道蛋白、β受体激动剂、上皮氯通道、α受体激动剂5个方面介绍了肺泡液体清除机制的研究进展,并简要介绍酸敏感离子通道及γ-氨基丁酸受体在肺泡液体清除中的作用机制。     

肺泡上皮在肺液体平衡中的作用

肺泡上皮的一个重要作用是组成肺泡毛细血管屏障，分泌表面活性物质降低肺表面张力，清除肺水肿。肺泡液体的转运是一个主动耗能过程，它是由于钠离子的主动重吸收产生了一个浓度梯度从而引起水的被动吸收。主动钠转运通过腔膜侧的钠通道和氯通道及基底膜侧的Na^＋-K＋-ATP酶调节。研究肺泡上皮细胞液体转运对肺水肿的治疗有重要临床意义。     

肺泡上皮液体清除功能的研究

肺泡上皮钠水主导转运的发现进一步完善了对肺水肿发病机理的认识,即肺水肿不再只受静水压力和上皮通透性的左右,还受上皮液体清除功能的影响。肺泡Ⅱ型细胞除了分泌表面活性物质外,还存在水通道、钠通道和Na,K-ATP酶,参与钠水的主动转运。现有的研究表明,这一功能受儿茶酚胺依赖性和非依赖性机制调节,为临床治疗肺水肿和肺损伤患者提供了重要的参考价值。但其确切的临床应用价值,还有待于进一步的深入研究。     

肺泡上皮液体清除功能的研究

肺泡上皮钠水主导转运的发现进一步完善了对肺水肿发病机理的认识，即肺水肿不再只受静水压力和上皮通透性的左右，还受上皮液体清除功能的影响。肺泡Ⅱ型细胞除了分泌表面活性物质外，还存在水通道、钠通道Ｎａ，Ｋ－ＡＴＰ酶，参与钠泊主动转运。现有的研究表明，这一功能受儿茶酚胺依赖性和非依赖性机制调节，为临床治疗肺水肿和肺损伤患者提供了重要的参考价值。但其确切的临床应用价值，还有待于进一小的深入研究。     

肺泡上皮蛋白清除机制的研究进展

蛋白的跨肺泡上皮屏障转运在肺水肿液的清除中发挥着重要作用。目前认为蛋白转运主要经两个途径：在低浓度时（白蛋白浓度〈5g／L）,蛋白转运主要是跨肺泡上皮细胞内吞途径;在高浓度时（白蛋白浓度〉50g／L）,蛋白转运主要是经上皮细胞侧面扩散途径。另外,肺泡巨噬细胞吞噬分解机制可能在不溶性蛋白的清除中起重要作用。     

肺泡液体清除率与囊性纤维跨膜电导调节因子氯通道的关系

急性肺损伤与急性呼吸窘迫综合征是同一疾病的不同发展阶段,肺水肿是两者的主要病理改变之一。肺水肿与肺泡液体清除率之间存在密切关系,提高肺泡液体清除率可以加快肺泡水肿液体的吸收。大量研究表明,上皮钠通道和囊性纤维跨膜电导调节因子氯通道是参与肺泡水肿液体清除过程的重要通道,它们的缺失或功能障碍会导致肺泡水肿液体的清除受阻。本文就肺泡液体清除机制及上述两种通道在这一过程中所发挥的作用做一阐述。     

β肾上腺素能受体激动剂对离体大鼠肺泡液体清除率的作用

目的探讨β1肾上腺素能受体激动剂地诺帕明、β2肾上腺素能受体激动剂特布他林、β3肾上腺素能受体激动剂BRL37344对离体大鼠肺泡液体清除率(AFC)的作用及机制。方法5%白蛋白等渗生理盐水溶液和不同药物混合后灌注到离体大鼠的肺泡腔内,根据灌注前及其孵育1h后白蛋白浓度的变化来计算大鼠AFC。结果基础AFC为6.9%±2.2%,地诺帕明、特布他林、BRL37344可显著提高AFC(分别为17.1%±2.4%、19.5%±1.2%、19.9%±2.5%)。β1肾上腺素能受体阻滞剂Atenolol可完全抑制地诺帕明提高AFC(6.1%±0.9%)的作用,但不能阻滞特布他林和BRL37344的作用。β2肾上腺素能受体阻滞剂ICI118551完全抑制了特布他林和BRL37344提高AFC(分别为5.7%±0.6%和7.8%±2.6%)的作用,部分抑制了地诺帕明的作用(AFC为12.7%±1.8%)。β3肾上腺素能受体阻滞剂SR59230A部分抑制了BRL37344和特布他林的作用(AFC分别为13.8%±3.1%和14.5%±3.4%),但不能阻滞地诺帕明的作用。结论地诺帕明、特布他林、BRL37344可以显著提高大鼠的AFC。但地诺帕明和特布他林是分别通过β1、β2肾上腺素能受体起作用;而BRL37344可能是通过β2肾上腺素能受体调节的。ICI118551和SR59230A可能分别具有抑制β1或β2肾上腺素能受体的作用。     

β2肾上腺素受体激动剂增强肺泡液体转运的信号转导机制进展

β2肾上腺素受体激动剂增强肺泡液体清除作用被高度关注,已在肺水肿和急性呼吸窘迫综合征患者中进行了多项临床实验.近年来其具体的信号转导机制的短时间作用和长时间作用两种途径都被进一步阐明,如前者高选择性Na+通道的膜插入机制,后者Na+,K+-ATP酶的转录后调节机制,为肺水肿治疗药物的开发奠定了理论基础.     

苯肾上腺素对低氧肺损伤大鼠肺泡液体清除的作用

目的探讨α肾上腺素能受体激动剂苯肾上腺素对低氧肺损伤大鼠肺泡液体清除率(AFC)的作用及机制。方法低氧大鼠暴露于10%的氧浓度,分别于24 h和48 h测定AFC、总肺水量(TLW)。苯肾上腺素分别与α1受体阻滞剂哌唑嗪、α2受体阻滞剂育亨宾、β1受体阻滞剂阿替洛尔、β2受体阻滞剂ICI-118551、钠通道阻断剂氨氯吡咪及Na+-K+-ATP酶阻断剂哇巴因混合后灌注到低氧48 h大鼠的肺泡腔内,测定AFC的变化。结果大鼠暴露于10%的氧浓度24 h后AFC(17.09±2.36)%/h与正常大鼠AFC(16.85±2.87)%/h比较没有明显变化;48 h时AFC(8.41±2.67)%/h明显降低。苯肾上腺素能明显增加低氧大鼠AFC。苯肾上腺素增加低氧大鼠AFC的作用能够被哌唑嗪、阿替洛尔、ICI-118551、氨氯吡咪和哇巴因抑制。结论α肾上腺素能受体激动剂苯肾上腺素通过调节Na+-K+-ATP酶及钠通道的活性增加低氧肺损伤大鼠肺泡液体清除能力,促进肺水肿液的吸收。     

Adenosine regulation of alveolar fluid clearance

Adenosine is a purine nucleoside that regulates cell function through G protein-coupled receptors that activate or inhibit adenylyl cyclase. Based on the understanding that cAMP regulates alveolar epithelial active Na(+) transport, we hypothesized that adenosine and its receptors have the potential to regulate alveolar ion transport and airspace fluid content. Herein, we report that type 1 (A(1)R), 2a (A(2a)R), 2b (A(2b)R), and 3 (A(3)R) adenosine receptors are present in rat and mouse lungs and alveolar type 1 and 2 epithelial cells (AT1 and AT2). Rat AT2 cells generated and produced cAMP in response to adenosine, and micromolar concentrations of adenosine were measured in bronchoalveolar lavage fluid from mice. Ussing chamber studies of rat AT2 cells indicated that adenosine affects ion transport through engagement of A(1)R, A(2a)R, and/or A(3)R through a mechanism that increases CFTR and amiloride-sensitive channel function. Intratracheal instillation of low concentrations of adenosine (< or =10(-8)M) or either A(2a)R- or A(3)R-specific agonists increased alveolar fluid clearance (AFC), whereas physiologic concentrations of adenosine (> or =10(-6)M) reduced AFC in mice and rats via an A(1)R-dependent pathway. Instillation of a CFTR inhibitor (CFTR(inh-172)) attenuated adenosine-mediated down-regulation of AFC, suggesting that adenosine causes Cl(-) efflux by means of CFTR. These studies report a role for adenosine in regulation of alveolar ion transport and fluid clearance. These findings suggest that physiologic concentrations of adenosine allow the alveolar epithelium to counterbalance active Na(+) absorption with Cl(-) efflux through engagement of the A(1)R and raise the possibility that adenosine receptor ligands can be used to treat pulmonary edema.     

Patterns of alveolar fluid clearance in heart failure

Alveolar fluid clearance (AFC) is important in keeping the airspaces free of edema. This process is accomplished via passive and active transport of Na(+) across the alveolo-capillary barrier mostly by apical Na(+) channels and basolateral Na,K-ATPases, respectively. Patterns of alveolar fluid clearance were found to be decreased in acutely elevated left atrial pressures, possibly due to the inhibition of alveolar epithelial active sodium transport. On the other hand, chronic elevation of pulmonary capillary pressure, such as seen in experimental and clinical congestive heart failure, increases alveolar fluid clearance most likely secondary to upregulation of active sodium transport.     

肺泡内水肿液清除及其干预机制的研究进展

肺泡上皮细胞的钠水转运系统由钠通道、Na~ -K~ -ATP酶和水通道等组成。肺泡内水肿液主要由钠水转运系统主动转运而重吸收。静水压性肺水肿和通透性肺水肿都可能存在肺泡内钠水重吸收障碍。对肺泡内液体重吸收的干预措施存在儿茶酚胺依赖和非儿茶酚胺依赖两类机制。儿茶酚胺依赖的β_2-受体激动剂和非儿茶酚胺依赖的糖皮质激素、甲状腺素、胰岛素、醛固酮、雌激素及生长因子等均可增加肺泡内钠水清除。     

Rapid alveolar epithelial fluid clearance following lung lavage in pulmonary alveolar proteinosis.

STUDY OBJECTIVE: To measure the in vivo rate of alveolar epithelial fluid clearance of the human lung in patients with pulmonary alveolar phospholipoproteinosis (PAP). DESIGN: Prospective clinical study. SETTING: The medical-surgical ICUs of a university teaching hospital. PATIENTS: Four patients with idiopathic PAP requiring therapeutic lung lavage. INTERVENTIONS: Large-volume lung lavage with isotonic saline solution using fiberoptic bronchoscopy followed by serial sampling of alveolar fluid using a wedged bronchial catheter. Measurements and results: The rate of alveolar epithelial fluid clearance was calculated by measuring the concentration of protein in sequential samples. Alveolar epithelial fluid clearance over the first hour after lung lavage was 53 +/- 14% (mean +/- SD). Sequential samples in two patients indicated a sustained high rate of clearance over several hours. Plasma and alveolar fluid epinephrine levels were in the normal range in two patients. CONCLUSIONS AND SIGNIFICANCE: Alveolar fluid clearance is rapid after lung lavage in patients with PAP and appears to be driven by catecholamine-independent mechanisms. The rapid rate of alveolar epithelial fluid transport explains why patients with PAP tolerate large-volume lung lavage.     

急性肺损伤时大鼠肺泡液体清除率的变化

目的 制备盐酸吸入性急性肺损伤动物模型，测定其肺泡液体清除率。方法 32只大鼠随机分为4组，对照组滴入pH为7.4的5％等渗白蛋白溶液，酸吸入组分别滴注pH为7.0、4.5、2.5的5％等渗白蛋白溶液，机械通气1h后，测定其动脉血气、肺泡上皮屏障的通透性、肺泡液体清除率。结果 当滴注液pH值为7.0时，其肺泡上皮对蛋白的通透性和对液体的清除率与对照组接近，动脉血氧分压无下降（P＞0.05）；pH值为4.5、2.5时，其肺泡上皮对蛋白的通透性和对液体清除率较对照组及pH7.0组低，动脉血氧分压明显下降（P＜0.05）。结论 肺泡上皮对酸损伤有一定的抵抗能力，高浓度盐酸溶液可损伤肺泡上皮和肺泡上皮屏障，使肺泡内液体不能及时清除，形成肺水肿。     

Endogenous catecholamine stimulates alveolar fluid clearance in rats with acute pancreatitis

Background and objective: Acute pancreatitis causes pulmonary oedema with the accumulation of fluid in the alveolar spaces, possibly due to reduced clearance. This study tested the hypothesis that acute pancreatitis decreases alveolar fluid clearance in a rat model of pulmonary oedema during acute pancreatitis. Methods: Acute pancreatitis was induced by a retrograde injection of 5% taurocholate sodium (0.2 mL) into the common bile duct. The lungs were isolated 4, 24 and 48 h after the induction of acute pancreatitis and alveolar fluid clearance was measured in the absence of pulmonary perfusion. Results: Alveolar fluid clearance increased to 31.0 ± 3.5% of instilled volume/h in rats with acute pancreatitis for 4 h compared with 17.3 ± 1.0% of instilled volume/h in sham rats (P < 0.01), then returned to the control level 48 h after acute pancreatitis (16.0 ± 4.1% of instilled volume/h). In contrast, the lung water to dry lung weight ratio decreased maximally 24 h after acute pancreatitis (P < 0.01), then returned to the control level 48 h after acute pancreatitis. The plasma epinephrine levels increased to 25‐fold higher in rats with acute pancreatitis for 4 h than in sham rats without acute pancreatitis. Prazosin (an α₁‐adrenergic antagonist, 10^?4 mol/L), yohimbine (an α₂‐adrenergic antagonist, 10^?4 mol/L) or a bilateral adrenalectomy inhibited the increase in part, a combination of prazosin (10^?4 mol/L) and yohimbine (10^?4 mol/L) completely inhibited the increase in alveolar fluid clearance in rats after acute pancreatitis for 4 h, whereas propranolol (a β‐adrenergic antagonist, 10^?4 mol/L) had no effect. Conclusions: Endogenous catecholamine stimulates α‐adrenoceptors and increases alveolar fluid clearance in rats with acute pancreatitis.