title: Phosphatidylinositol 4,5-bisphosphate stimulates alveolar epithelial fluid clearance in male and female adult rats.
abstract: 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.
authors.affiliation: Dept. of Biological Sciences, Kent State Univ., Kent, OH 44242, USA. ekooijma@kent.edu
authors.forename: Edgar E
authors.initials: EE
authors.lastname: Kooijman
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Kuzenko
authors.forename: Denghuang
authors.initials: D
authors.lastname: Gong
authors.forename: Michael D
authors.initials: MD
authors.lastname: Best
authors.forename: Hans G
authors.initials: HG
authors.lastname: Folkesson
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000418:Albumins / Q000009:adverse effects; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001826:Body Fluids / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006439:Hemodynamics; D008297:Male; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013726:Terbutaline / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D000418:Albumins; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D034741:RNA, Small Interfering; D011943:Receptors, Adrenergic, beta; D026941:Sodium Channel Blockers; D000584:Amiloride; D011433:Propranolol; D013726:Terbutaline