Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4

Joel Michalski, Nobuhiro Kanaji, Xiang-de Liu, Steve Nogel, Xingqi Wang, Hesham E Basma, Masanori Nakanishi, Tadashi Sato, Yoko Gunji, Maha Fahrid, Amy Nelson, Kai Christian Muller, Olaf Holz, Helgo Magnussen, Klaus F. Rabe, Myron Lee Toews, Stephen I. Rennard

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The etiology of chronic obstructive pulmonary disease (COPD) is complex and involves an aberrant inflammatory response. Prostaglandin (PG)E2 is elevated in COPD, is a key modulator of lung fibroblast functions, and may influence COPD progression. Most studies evaluating the effects of PGE2 on lung fibroblasts have used acute exposures. The current study evaluated whether longer-term exposure would induce attenuation of PGE2 signaling as part of an autoregulatory pathway. Human fetal lung fibroblasts were pretreated with PGE2 for 24 hours, and migration and cAMP accumulation in response to acute stimulation with PGE2 were assessed. Fibroblasts from adults with and without COPD were pretreated, and migration was assessed. PGE2 pretreatment attenuated subsequent PGE2-mediated inhibition of chemotaxis and cAMP stimulation. This attenuation was predominantly due to an increase in phosphodiesterase (PDE)4-mediated degradation of cAMP rather than to decreased activation of PGE2 receptors (receptor desensitization). Albuterol- and iloprost-mediated signaling were also attenuated after PGE2 pretreatment, suggesting that activation of PDE4 was able to broadly modulate multiple cAMP-coupled pathways. Lung fibroblasts from adult control subjects pretreated with PGE2 also developed attenuation of PGE2-mediated inhibition of chemotaxis. In contrast, fibroblasts obtained from patients with COPD maintained inhibitory PGE2 signaling after PGE2 pretreatment. These data identify a PDE4-mediated attenuation of PGE2 inhibitory signaling in normal fibroblasts that appears to be altered in COPD fibroblasts. These alterations may contribute to COPD pathogenesis and could provide novel therapeutic targets.

Original languageEnglish (US)
Pages (from-to)729-737
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume47
Issue number6
DOIs
StatePublished - Dec 1 2012

Fingerprint

Type 4 Cyclic Nucleotide Phosphodiesterase
Fibroblasts
Dinoprostone
Pulmonary diseases
Lung
Chronic Obstructive Pulmonary Disease
Cell Migration Inhibition
Chemical activation
Prostaglandin E Receptors
Iloprost
Albuterol

Keywords

  • COPD
  • Desensitization
  • Fibroblast
  • PGE2

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4. / Michalski, Joel; Kanaji, Nobuhiro; Liu, Xiang-de; Nogel, Steve; Wang, Xingqi; Basma, Hesham E; Nakanishi, Masanori; Sato, Tadashi; Gunji, Yoko; Fahrid, Maha; Nelson, Amy; Muller, Kai Christian; Holz, Olaf; Magnussen, Helgo; Rabe, Klaus F.; Toews, Myron Lee; Rennard, Stephen I.

In: American journal of respiratory cell and molecular biology, Vol. 47, No. 6, 01.12.2012, p. 729-737.

Research output: Contribution to journalArticle

Michalski, J, Kanaji, N, Liu, X, Nogel, S, Wang, X, Basma, HE, Nakanishi, M, Sato, T, Gunji, Y, Fahrid, M, Nelson, A, Muller, KC, Holz, O, Magnussen, H, Rabe, KF, Toews, ML & Rennard, SI 2012, 'Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4', American journal of respiratory cell and molecular biology, vol. 47, no. 6, pp. 729-737. https://doi.org/10.1165/rcmb.2012-0057OC
Michalski, Joel ; Kanaji, Nobuhiro ; Liu, Xiang-de ; Nogel, Steve ; Wang, Xingqi ; Basma, Hesham E ; Nakanishi, Masanori ; Sato, Tadashi ; Gunji, Yoko ; Fahrid, Maha ; Nelson, Amy ; Muller, Kai Christian ; Holz, Olaf ; Magnussen, Helgo ; Rabe, Klaus F. ; Toews, Myron Lee ; Rennard, Stephen I. / Attenuation of inhibitory prostaglandin E2 signaling in human lung fibroblasts is mediated by phosphodiesterase 4. In: American journal of respiratory cell and molecular biology. 2012 ; Vol. 47, No. 6. pp. 729-737.
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AU - Fahrid, Maha

AU - Nelson, Amy

AU - Muller, Kai Christian

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N2 - The etiology of chronic obstructive pulmonary disease (COPD) is complex and involves an aberrant inflammatory response. Prostaglandin (PG)E2 is elevated in COPD, is a key modulator of lung fibroblast functions, and may influence COPD progression. Most studies evaluating the effects of PGE2 on lung fibroblasts have used acute exposures. The current study evaluated whether longer-term exposure would induce attenuation of PGE2 signaling as part of an autoregulatory pathway. Human fetal lung fibroblasts were pretreated with PGE2 for 24 hours, and migration and cAMP accumulation in response to acute stimulation with PGE2 were assessed. Fibroblasts from adults with and without COPD were pretreated, and migration was assessed. PGE2 pretreatment attenuated subsequent PGE2-mediated inhibition of chemotaxis and cAMP stimulation. This attenuation was predominantly due to an increase in phosphodiesterase (PDE)4-mediated degradation of cAMP rather than to decreased activation of PGE2 receptors (receptor desensitization). Albuterol- and iloprost-mediated signaling were also attenuated after PGE2 pretreatment, suggesting that activation of PDE4 was able to broadly modulate multiple cAMP-coupled pathways. Lung fibroblasts from adult control subjects pretreated with PGE2 also developed attenuation of PGE2-mediated inhibition of chemotaxis. In contrast, fibroblasts obtained from patients with COPD maintained inhibitory PGE2 signaling after PGE2 pretreatment. These data identify a PDE4-mediated attenuation of PGE2 inhibitory signaling in normal fibroblasts that appears to be altered in COPD fibroblasts. These alterations may contribute to COPD pathogenesis and could provide novel therapeutic targets.

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