Dataset Information

Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia.

ABSTRACT:

Rationale

Prostaglandin (PG) E2, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE2 synthesis, there is little information about their responsiveness to this lipid mediator.

Objectives

To compare responses to PGE2 in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DPLD) fibroblasts.

Methods

Fibroblasts were grown in vitro from well characterized control (n = 7), UIP (n = 17), or other DPLD (n = 13) lung tissue. The effects of PGE2 on fibroblast proliferation and collagen expression were determined.

Measurements and main results

Only 3 of 12 UIP fibroblast lines exhibited PGE2-mediated inhibition of both collagen synthesis and cell proliferation, as opposed to 6 of 6 nonfibrotic control cell lines. The degree of PGE2 resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE2, whereas other DPLD fibroblasts manifested a degree of resistance intermediate to control and UIP. The resistance to suppression of collagen expression correlated with worse lung function. Molecular mechanisms for resistance included altered E prostanoid receptor profiles and diminished expression of the downstream kinase, protein kinase A.

Conclusions

The recognition that UIP fibroblasts manifest variable refractoriness to PGE2 suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.

SUBMITTER: Huang SK

PROVIDER: S-EPMC2176116 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia.

Huang Steven K SK Wettlaufer Scott H SH Hogaboam Cory M CM Flaherty Kevin R KR Martinez Fernando J FJ Myers Jeffrey L JL Colby Thomas V TV Travis William D WD Toews Galen B GB Peters-Golden Marc M

American journal of respiratory and critical care medicine 20071004 1

<h4>Rationale</h4>Prostaglandin (PG) E2, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE2 synthesis, there is little information about their responsiveness to this lipid mediator.<h4>Objectives</h4>To compare responses to PGE2 in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DP ...[more]

PMID: 17916807

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Project description:PURPOSE:To conduct a meta-analysis to determine specific computed tomography (CT) patterns and clinical features that discriminate between nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). MATERIALS AND METHODS:The PubMed/Medline and Embase databases were searched for studies describing the radiological patterns of UIP and NSIP in chest CT images. Only studies involving histologically confirmed diagnoses and a consensus diagnosis by an interstitial lung disease (ILD) board were included in this analysis. The radiological patterns and patient demographics were extracted from suitable articles. We used random-effects meta-analysis by DerSimonian & Laird and calculated pooled odds ratios for binary data and pooled mean differences for continuous data. RESULTS:Of the 794 search results, 33 articles describing 2,318 patients met the inclusion criteria. Twelve of these studies included both NSIP (338 patients) and UIP (447 patients). NSIP-patients were significantly younger (NSIP: median age 54.8 years, UIP: 59.7 years; mean difference (MD) -4.4; p = 0.001; 95% CI: -6.97 to -1.77), less often male (NSIP: median 52.8%, UIP: 73.6%; pooled odds ratio (OR) 0.32; p<0.001; 95% CI: 0.17 to 0.60), and less often smokers (NSIP: median 55.1%, UIP: 73.9%; OR 0.42; p = 0.005; 95% CI: 0.23 to 0.77) than patients with UIP. The CT findings from patients with NSIP revealed significantly lower levels of the honeycombing pattern (NSIP: median 28.9%, UIP: 73.4%; OR 0.07; p<0.001; 95% CI: 0.02 to 0.30) with less peripheral predominance (NSIP: median 41.8%, UIP: 83.3%; OR 0.21; p<0.001; 95% CI: 0.11 to 0.38) and more subpleural sparing (NSIP: median 40.7%, UIP: 4.3%; OR 16.3; p = 0.005; 95% CI: 2.28 to 117). CONCLUSION:Honeycombing with a peripheral predominance was significantly associated with a diagnosis of UIP. The NSIP pattern showed more subpleural sparing. The UIP pattern was predominantly observed in elderly males with a history of smoking, whereas NSIP occurred in a younger patient population.

Project description:BACKGROUND:Mortality is similarly high among individuals with usual interstitial pneumonia (UIP) due to idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF). Circulating anti-nuclear antibodies (ANA) are commonly found in this patient population, suggesting possible aberrant immune activation. Because an environment of oxidative stress can result from immunologic activation, we hypothesized that ANA positive patients with UIP would have improved outcome when exposed to the antioxidant N-acetylcysteine (NAC) compared to ANA negative patients. METHODS:A single center, retrospective cohort analysis was performed. Patients with UIP due to IPF and IPAF were stratified according to ANA status to and NAC exposure. Transplant-free survival (TFS) was assessed using the Kaplan-Meier estimator and multivariable Cox regression adjusted for diagnosis, gender/age/physiology score, immunosuppressant exposure and anti-fibrotic exposure. RESULTS:Of 293 individuals with UIP due to IPF (74%) or IPAF (26%), NAC exposure was documented in 58 (19.8%). Among NAC exposed individuals, 33 (56.9%) were ANA seropositive and 25 (43.1%) were seronegative. NAC exposure was associated with improved TFS survival among ANA seropositive individuals in unadjusted analysis (plogrank?=?0.02) and after multi-variable adjustment (HR 0.51, 95% CI 0.30-0.87; p?=?0.01). There was no association between NAC exposure and TFS in ANA seronegative individuals (HR 1.26, 95% CI 0.69-2.32; p?=?0.45). Formal interaction testing confirmed NAC*ANA interaction (p?=?0.04) and sensitivity analysis demonstrated an increasing effect size associated with NAC therapy as ANA titer increased. Among patients with available genetic data, a marginally higher proportion of ANA positive patients (p?=?0.08) carried the rs3750920 (TOLLIP) genotype previously shown to predict favorable outcome in NAC exposed patients. CONCLUSION:NAC exposure is associated with improved transplant-free survival ANA positive patients with UIP. These findings support the prospective collection of ANA data in in future NAC clinical trials performed in patients with UIP.

Dataset Information

Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Variable prostaglandin E2 resistance in fibroblasts from patients with usual interstitial pneumonia.

Similar Datasets

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