PMID- 22452977
OWN - NLM
STAT- MEDLINE
DCOM- 20120823
LR  - 20220408
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 13
IP  - 1
DP  - 2012 Mar 27
TI  - Combination of roflumilast with a beta-2 adrenergic receptor agonist inhibits 
      proinflammatory and profibrotic mediator release from human lung fibroblasts.
PG  - 28
LID - 10.1186/1465-9921-13-28 [doi]
AB  - BACKGROUND: Small airway narrowing is an important pathology which impacts lung 
      function in chronic obstructive pulmonary disease (COPD). The accumulation of 
      fibroblasts and myofibroblasts contribute to inflammation, remodeling and 
      fibrosis by production and release of mediators such as cytokines, profibrotic 
      factors and extracellular matrix proteins. This study investigated the effects of 
      the phosphodiesterase 4 inhibitor roflumilast, combined with the long acting beta2 
      adrenergic agonist indacaterol, both approved therapeutics for COPD, on 
      fibroblast functions that contribute to inflammation and airway fibrosis. 
      METHODS: The effects of roflumilast and indacaterol treatment were characterized 
      on transforming growth factor beta1 (TGFbeta1)-treated normal human lung fibroblasts 
      (NHLF). NHLF were evaluated for expression of the profibrotic mediators 
      endothelin-1 (ET-1) and connective tissue growth factor (CTGF), expression of the 
      myofibroblast marker alpha smooth muscle actin, and fibronectin (FN) secretion. 
      Tumor necrosis factor-alpha (TNF-alpha) was used to induce secretion of chemokine C-X-C 
      motif ligand 10 (CXCL10), chemokine C-C motif ligand 5 (CCL5) and granulocyte 
      macrophage colony-stimulating factor (GM-CSF) from NHLF and drug inhibition was 
      assessed. RESULTS: Evaluation of roflumilast (1-10 muM) showed no significant 
      inhibition alone on TGFbeta1-induced ET-1 and CTGF mRNA transcripts, ET-1 and FN 
      protein production, alpha smooth muscle expression, or TNF-alpha-induced secretion of 
      CXCL10, CCL5 and GM-CSF. A concentration-dependent inhibition of ET-1 and CTGF 
      was shown with indacaterol treatment, and a submaximal concentration was chosen 
      for combination studies. When indacaterol (0.1 nM) was added to roflumilast, 
      significant inhibition was seen on all inflammatory and fibrotic mediators 
      evaluated, which was superior to the inhibition seen with either drug alone. 
      Roflumilast plus indacaterol combination treatment resulted in significantly 
      elevated phosphorylation of the transcription factor cAMP response 
      element-binding protein (CREB), an effect that was protein kinase A-dependent. 
      Inhibition of protein kinase A was also found to reverse the inhibition of 
      indacaterol and roflumilast on CTGF. CONCLUSIONS: These results demonstrate that 
      addition of roflumilast to a LABA inhibits primary fibroblast/myofibroblast 
      function and therapeutically this may impact lung fibroblast proinflammatory and 
      profibrotic mediator release which contributes to small airway remodeling and 
      airway obstruction in COPD.
FAU - Tannheimer, Stacey L
AU  - Tannheimer SL
AD  - Respiratory Research, Gilead Sciences, 199 East Blaine St, Seattle, WA 98102, 
      USA. Tannheimer@gilead.com
FAU - Wright, Clifford D
AU  - Wright CD
FAU - Salmon, Michael
AU  - Salmon M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120327
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (ACTA2 protein, human)
RN  - 0 (Actins)
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Aminopyridines)
RN  - 0 (Benzamides)
RN  - 0 (CCL5 protein, human)
RN  - 0 (CCN2 protein, human)
RN  - 0 (CXCL10 protein, human)
RN  - 0 (Chemokine CCL5)
RN  - 0 (Chemokine CXCL10)
RN  - 0 (Cyclopropanes)
RN  - 0 (Endothelin-1)
RN  - 0 (Fibronectins)
RN  - 0 (Indans)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0 (Quinolones)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0P6C6ZOP5U (Roflumilast)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - 8OR09251MQ (indacaterol)
SB  - IM
MH  - Actins/metabolism
MH  - Adrenergic beta-2 Receptor Agonists/*pharmacology
MH  - Aminopyridines/*pharmacology
MH  - Benzamides/*pharmacology
MH  - Cells, Cultured
MH  - Chemokine CCL5/metabolism
MH  - Chemokine CXCL10/metabolism
MH  - Connective Tissue Growth Factor/metabolism
MH  - Cyclopropanes/pharmacology
MH  - Endothelin-1/metabolism
MH  - Fibroblasts/cytology/drug effects/*metabolism
MH  - Fibronectins/metabolism
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
MH  - Humans
MH  - Indans/*pharmacology
MH  - Inflammation/metabolism/*prevention & control
MH  - Lung/cytology/drug effects/*metabolism
MH  - Phosphodiesterase 4 Inhibitors/*pharmacology
MH  - Pulmonary Fibrosis/metabolism/*prevention & control
MH  - Quinolones/*pharmacology
MH  - Transforming Growth Factor beta1/pharmacology
MH  - Tumor Necrosis Factor-alpha/pharmacology
PMC - PMC3342220
EDAT- 2012/03/29 06:00
MHDA- 2012/08/24 06:00
PMCR- 2012/03/27
CRDT- 2012/03/29 06:00
PHST- 2011/12/23 00:00 [received]
PHST- 2012/03/27 00:00 [accepted]
PHST- 2012/03/29 06:00 [entrez]
PHST- 2012/03/29 06:00 [pubmed]
PHST- 2012/08/24 06:00 [medline]
PHST- 2012/03/27 00:00 [pmc-release]
AID - 1465-9921-13-28 [pii]
AID - 10.1186/1465-9921-13-28 [doi]
PST - epublish
SO  - Respir Res. 2012 Mar 27;13(1):28. doi: 10.1186/1465-9921-13-28.