PMID- 20876748
OWN - NLM
STAT- MEDLINE
DCOM- 20110118
LR  - 20181201
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 336
IP  - 1
DP  - 2011 Jan
TI  - Macrolide antibiotics inhibit mucus secretion and calcium entry in Swine airway 
      submucosal mucous gland cells.
PG  - 178-87
LID - 10.1124/jpet.110.171561 [doi]
AB  - Macrolide antibiotics such as erythromycin (EM) and azithromycin (AZM) are 
      beneficial in the treatment of mucus hypersecretion in inflammatory pulmonary 
      diseases. Several indirect and direct mechanisms of action have been proposed. 
      This study investigates the direct effect of macrolides on secretory function of 
      isolated submucosal mucous gland cells (SMGCs). We hypothesize that macrolides 
      inhibit the calcium influx necessary for evoked mucus secretion. To test this, we 
      quantified mucin protein release using enzyme-linked immunosorbent assay, 
      calcium-activated K(+) (K(Ca)), and calcium-activated Cl(-) (Cl(Ca)) currents. We 
      measured nonselective cation current (NSCC) using whole-cell patch-clamp 
      techniques; intracellular calcium concentration ([Ca(2+)](i)) was measured using 
      fura-2 Ca(2+) imaging. We found that both EM and AZM are agonists at muscarinic 
      receptors. EM (10 muM) evoked a small but significant increase in mucin release 
      but inhibited the mucin release induced by subsequent acetylcholine (ACh) 
      treatment. Both EM and AZM (10 muM) evoked K(Ca) and Cl(Ca) whole-cell currents, 
      which were blocked by atropine. EM and AZM also accelerated the decay of inositol 
      trisphosphate-induced K(Ca) and Cl(Ca) currents without changing the peak current 
      amplitudes. Likewise, internal application of AZM (10 muM) enhanced the decay rate 
      of ACh-induced K(Ca) and Cl(Ca) currents. EM (1-10 muM) and AZM (0.1-10 muM) slowly 
      (over 25-30 min) inhibited thapsigargin (TG)-induced Ca(2+) entry when applied 
      during the plateau phase of Ca(2+) entry but blunted TG-induced Ca(2+) entry by 
      70% after a 5-min pretreatment before initiating calcium entry. EM blocked 
      TG-induced NSCC. We conclude that macrolide antibiotics are partial agonists at 
      muscarinic receptors but inhibit stimulated mucus release by inhibiting calcium 
      entry in SMGCs.
FAU - Lu, S
AU  - Lu S
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, Jackson, MS 39216-4505, USA.
FAU - Liu, H
AU  - Liu H
FAU - Farley, J M Sr
AU  - Farley JM Sr
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100928
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Macrolides)
RN  - 0 (Mucins)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/pharmacology
MH  - Calcium/*antagonists & inhibitors/metabolism
MH  - Macrolides/*pharmacology
MH  - Mucins/antagonists & inhibitors/metabolism
MH  - Mucus/*drug effects/*metabolism
MH  - Respiratory Mucosa/drug effects/metabolism
MH  - Submucous Plexus/drug effects/metabolism
MH  - Swine
MH  - Trachea/*drug effects/*metabolism
EDAT- 2010/09/30 06:00
MHDA- 2011/01/19 06:00
CRDT- 2010/09/30 06:00
PHST- 2010/09/30 06:00 [entrez]
PHST- 2010/09/30 06:00 [pubmed]
PHST- 2011/01/19 06:00 [medline]
AID - jpet.110.171561 [pii]
AID - 10.1124/jpet.110.171561 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2011 Jan;336(1):178-87. doi: 10.1124/jpet.110.171561. Epub 
      2010 Sep 28.