Dept. of Biological Sciences, Kent State Univ., Kent, OH 44242, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Nov;301(5):L804-11. doi: 10.1152/ajplung.00445.2010. Epub 2011 Aug 26.
Cell membrane phospholipids, like phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], can regulate epithelial Na channel (ENaC) activity. Gender differences in lung ENaC expression have also been demonstrated. However, the effects in vivo on alveolar fluid clearance are uncertain. Thus PI(4,5)P(2) effects on alveolar fluid clearance were studied in male and female rats. An isosmolar 5% albumin solution was intrapulmonary instilled; alveolar fluid clearance was studied for 1 h. Female rats had a 37 ± 19% higher baseline alveolar fluid clearance than male rats. Bilateral ovariectomy attenuated this gender difference. Compared with controls, PI(4,5)P(2) instillation (300 μM) increased alveolar fluid clearance by ∼93% in both genders. Amiloride or the specific αENaC small-interfering RNA inhibited baseline and PI(4,5)P(2)-stimulated alveolar fluid clearance in both genders, indicating a dependence on amiloride-sensitive pathways. The fraction of amiloride inhibition was greater in PI(4,5)P(2)-instilled rats (male: 64 ± 10%; female: 70 ± 11%) than in controls (male: 30 ± 6%; female: 44 ± 8%). PI(4,5)P(2) instillation lacked additional alveolar fluid clearance stimulation above that of terbutaline, nor did propranolol inhibit alveolar fluid clearance after PI(4,5)P(2) instillation, indicating that PI(4,5)P(2) stimulation was not secondary to endogenous β-adrenoceptor activation. PI(4,5)P(2) amine instillation resulted in an intermediate alveolar fluid clearance stimulation, suggesting that, to reach maximal alveolar fluid clearance stimulation, PI(4,5)P(2) must reside in cell membranes. In summary, PI(4,5)P(2) instillation upregulated in vivo alveolar fluid clearance similar to short-term β-adrenoceptor upregulation of alveolar fluid clearance. PI(4,5)P(2) stimulation was mediated partly by increased amiloride-sensitive Na transport. There exist important gender-related effects suggesting a female advantage that may have clinical implications for resolution of acute lung injury.
细胞膜磷脂，如磷脂酰肌醇 4,5-二磷酸[PI(4,5)P(2)]，可以调节上皮钠通道（ENaC）的活性。已经证明，肺 ENaC 的表达存在性别差异。然而，其对肺泡液清除的体内影响尚不确定。因此，本研究旨在探讨 PI(4,5)P(2)对肺泡液清除的影响。通过气管内滴注等渗 5%白蛋白溶液，研究了 1 小时内的肺泡液清除率。与雄性大鼠相比，雌性大鼠的基础肺泡液清除率高 37±19%。双侧卵巢切除术减弱了这种性别差异。与对照组相比，PI(4,5)P(2)滴注（300μM）使两性的肺泡液清除率分别增加了约 93%。阿米洛利或特异性αENaC 小干扰 RNA 抑制了两性的基础和 PI(4,5)P(2)刺激的肺泡液清除率，表明这依赖于阿米洛利敏感途径。PI(4,5)P(2)滴注大鼠（雄性：64±10%；雌性：70±11%）中阿米洛利抑制的比例大于对照组（雄性：30±6%；雌性：44±8%）。PI(4,5)P(2)滴注后，特布他林不能进一步增加肺泡液清除率，普萘洛尔也不能抑制 PI(4,5)P(2)滴注后的肺泡液清除率，这表明 PI(4,5)P(2)刺激不是继发于内源性β-肾上腺素能受体激活。PI(4,5)P(2)胺滴注导致肺泡液清除率呈中等刺激，这表明为了达到最大的肺泡液清除率刺激，PI(4,5)P(2)必须位于细胞膜上。总之，PI(4,5)P(2)滴注上调了体内肺泡液清除率，类似于短期β-肾上腺素能上调肺泡液清除率。PI(4,5)P(2)刺激部分是通过增加阿米洛利敏感的 Na 转运介导的。存在重要的性别相关影响，表明女性具有优势，这可能对急性肺损伤的清除具有临床意义。
