Fetal alveolar epithelial cells contain [D-Ala(2)]-deltorphin I-like immunoreactivity: delta- and mu-opiate receptors mediate opposite effects in developing lung

Am J Respir Cell Mol Biol. 2001 Oct;25(4):447-56. doi: 10.1165/ajrcmb.25.4.4072.


Opiate-like peptides can regulate many cellular functions. We now map [D-Ala(2)]deltorphin I (DADTI)-like immunoreactivity (DADTI-LI) in developing mouse lung and analyze potential functional roles. Most DADTI-LI-positive cells were alveolar cells negative for prosurfactant protein (proSP)-C immunoreactivity. Peak numbers of DADTI-LI-positive cells occurred on embryonic Day 18, decreasing postnatally. To analyze developmental effects of DADTI, e17-18 lung explants were treated with [D-Ala(2)]deltorphin II (DADTII, soluble DADTI analogue, delta-receptor-specific) versus dermorphin (mu-receptor-specific). Type II pneumocyte differentiation, assessed by [(3)H]choline incorporation into saturated phosphatidylcholine and proSP-C immunostaining, was inhibited by DADTII but stimulated by dermorphin. Cell proliferation, measured as [(3)H]-thymidine incorporation and proliferating cell nuclear antigen immunostaining, was stimulated by DADTII and inhibited by dermorphin. All effects were dose-dependent. DADTII-inhibited choline incorporation was reversed by the delta-blocker, naltrindole. Unexpectedly, DADTII-stimulated thymidine incorporation was augmented by naltrindole and reversed by naloxone (mu-blocker). Although dermorphin-stimulated choline incorporation was appropriately blocked by binaltorphimine, dermorphin-inhibited thymidine incorporation was reversed by delta, kappa-, or mu-blockers. The delta- and mu-receptor messenger RNAs occurred pre- and postnatally, whereas kappa-receptor transcripts occurred mainly prenatally. All three receptor proteins were present in epithelial and mesenchymal cells in e18 lung. Thus, DADTI-LI from proSP-C-immunonegative alveolar cells could regulate development via both direct and indirect effects involving multiple opiate receptors.

Publication types

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

MeSH terms

  • Animals
  • Choline / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Intercellular Signaling Peptides and Proteins
  • Lung / drug effects
  • Lung / embryology
  • Mice
  • Oligopeptides / immunology*
  • Oligopeptides / pharmacology
  • Organ Culture Techniques
  • Peptides / immunology
  • Pregnancy
  • Proliferating Cell Nuclear Antigen / immunology
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / embryology*
  • Pulmonary Alveoli / immunology
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Surfactants / immunology
  • Receptors, Opioid / genetics*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / embryology*
  • Respiratory Mucosa / immunology*
  • Thymidine / pharmacokinetics


  • Intercellular Signaling Peptides and Proteins
  • Oligopeptides
  • Peptides
  • Proliferating Cell Nuclear Antigen
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Surfactants
  • Receptors, Opioid
  • Sftpc protein, mouse
  • deltorphin II, Ala(2)-
  • Choline
  • Thymidine