beta(2)-adrenergic receptor overexpression increases alveolar fluid clearance and responsiveness to endogenous catecholamines in rats

Circ Res. 2001 Nov 9;89(10):907-14. doi: 10.1161/hh2201.100204.

Abstract

beta-Adrenergic agonists accelerate the clearance of alveolar fluid by increasing the expression and activity of epithelial solute transport proteins such as amiloride-sensitive epithelial Na(+) channels (ENaC) and Na,K-ATPases. Here we report that adenoviral-mediated overexpression of a human beta(2)-adrenergic receptor (beta(2)AR) cDNA increases beta(2)AR mRNA, membrane-bound receptor protein expression, and receptor function (procaterol-induced cAMP production) in human lung epithelial cells (A549). Receptor overexpression was associated with increased catecholamine (procaterol)-responsive active Na(+) transport and increased abundance of Na,K-ATPases in the basolateral cell membrane. beta(2)AR gene transfer to the alveolar epithelium of normal rats improved membrane-bound beta(2)AR expression and function and increased levels of ENaC (alpha subunit) abundance and Na,K-ATPases activity in apical and basolateral cell membrane fractions isolated from the peripheral lung, respectively. Alveolar fluid clearance (AFC), an index of active Na(+) transport, in beta(2)AR overexpressing rats was up to 100% greater than sham-infected controls and rats infected with an adenovirus that expresses no cDNA. The addition of the beta(2)AR-specific agonist procaterol to beta(2)AR overexpressing lungs did not increase AFC further. AFC in beta(2)AR overexpressing lungs from adrenalectomized or propranolol-treated rats revealed clearance rates that were the same or less than normal, untreated, sham-infected controls. These experiments indicate that alveolar beta(2)AR overexpression improves beta(2)AR function and maximally upregulates beta-agonist-responsive active Na(+) transport by improving responsiveness to endogenous catecholamines. These studies suggest that upregulation of beta(2)AR function may someday prove useful for the treatment of pulmonary edema.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Carrier Proteins / metabolism
  • Catecholamines / metabolism*
  • Catecholamines / pharmacology
  • Cell Line
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • DNA, Complementary / administration & dosage
  • DNA, Complementary / genetics
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Sodium Channels
  • Gene Transfer, Horizontal
  • Humans
  • Ion Transport / drug effects
  • Lung / cytology
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Mucociliary Clearance / physiology*
  • Procaterol / pharmacology
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta-2 / administration & dosage
  • Receptors, Adrenergic, beta-2 / biosynthesis*
  • Receptors, Adrenergic, beta-2 / genetics
  • Sodium / metabolism
  • Sodium Channels / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism

Substances

  • Carrier Proteins
  • Catecholamines
  • DNA, Complementary
  • Epithelial Sodium Channels
  • RNA, Messenger
  • Receptors, Adrenergic, beta-2
  • Sodium Channels
  • Sodium
  • Sodium-Potassium-Exchanging ATPase
  • Procaterol