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Aberrant innate immune sensing leads to the rapid progression of idiopathic pulmonary fibrosis.

Hogaboam CM, Trujillo G, Martinez FJ - Fibrogenesis Tissue Repair (2012)

Bottom Line: Disparate physiological approaches have also been taken to identify patients at risk of mortality, with varying results.Finally, CpG DNA exacerbated fibrosis in an in vivo model initiated by the adoptive transfer of primary fibroblasts derived from patients who exhibited rapidly progressing fibrosis.Together, these data suggested that TLR9 activation via hypomethylated DNA might be an important mechanism in promoting fibrosis particularly in patients prone to rapidly progressing IPF.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, USA.

ABSTRACT
Novel approaches are needed to define subgroups of patients with Idiopathic pulmonary fibrosis (IPF) at risk for acute exacerbations and/or accelerated progression of this generally fatal disease. Progression of disease is an integral component of IPF with a median survival of 3 to 5 years. Conversely, a high degree of variability in disease progression has been reported among series. The characteristics of patients at risk of earlier death predominantly rely on baseline HRCT appearance, but this concept that has been challenged. Disparate physiological approaches have also been taken to identify patients at risk of mortality, with varying results. We hypothesized that the rapid decline in lung function in IPF may be a consequence of an abnormal host response to pathogen-associated molecular patterns (PAMPs), leading to aberrant activation in fibroblasts and fibrosis. Analysis of upper and lower lobe surgical lung biopsies (SLBs) indicated that TLR9, a hypomethylated CpG DNA receptor, is prominently expressed at the transcript and protein level, most notably in biopsies from rapidly progressive IPF patients. Surprisingly, fibroblasts appeared to be a major cellular source of TLR9 expression in IPF biopsies from this group of progressors. Further, CpG DNA promoted profibrotic cytokine and chemokine synthesis in isolated human IPF fibroblasts, most markedly again in cells from patients with the rapidly progressive IPF phenotype, in a TLR9-dependent manner. Finally, CpG DNA exacerbated fibrosis in an in vivo model initiated by the adoptive transfer of primary fibroblasts derived from patients who exhibited rapidly progressing fibrosis. Together, these data suggested that TLR9 activation via hypomethylated DNA might be an important mechanism in promoting fibrosis particularly in patients prone to rapidly progressing IPF.

No MeSH data available.


Related in: MedlinePlus

A. An inconsistent change in FVC is noted in IPF patients, who died acutely in the placebo arm of a large, randomized therapeutic trial. B. Serial FVC change in IPF patients, who died subacutely in the placebo arm of a large, randomized therapeutic trial.
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Figure 1: A. An inconsistent change in FVC is noted in IPF patients, who died acutely in the placebo arm of a large, randomized therapeutic trial. B. Serial FVC change in IPF patients, who died subacutely in the placebo arm of a large, randomized therapeutic trial.

Mentions: In the placebo arm of a large therapeutic trial, we reported that 36 (21.4%) IPF patients died during 72 weeks of follow-up [3]. Death was considered by the primary investigators to be IPF-related in 89% of the cases. In 47% of these IPF-related deaths, investigators characterized disease progression as acute or abrupt suggesting that an acute exacerbation of disease was the reason for death. Figure 1 illustrates the longitudinal change in FVC among the IPF patients who died abruptly (Panel A) and those that died due to sub-acute deterioration (Panel B). A decrease in FVC was not consistently noted in patients who died acutely. These data highlight limitations of physiological deterioration in predicting mortality and suggested that additional endpoints are needed to define longitudinal phenotype behavior in IPF. The occurrence of acute exacerbations in IPF is an appropriate event-based component of a marker for disease progression.


Aberrant innate immune sensing leads to the rapid progression of idiopathic pulmonary fibrosis.

Hogaboam CM, Trujillo G, Martinez FJ - Fibrogenesis Tissue Repair (2012)

A. An inconsistent change in FVC is noted in IPF patients, who died acutely in the placebo arm of a large, randomized therapeutic trial. B. Serial FVC change in IPF patients, who died subacutely in the placebo arm of a large, randomized therapeutic trial.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368762&req=5

Figure 1: A. An inconsistent change in FVC is noted in IPF patients, who died acutely in the placebo arm of a large, randomized therapeutic trial. B. Serial FVC change in IPF patients, who died subacutely in the placebo arm of a large, randomized therapeutic trial.
Mentions: In the placebo arm of a large therapeutic trial, we reported that 36 (21.4%) IPF patients died during 72 weeks of follow-up [3]. Death was considered by the primary investigators to be IPF-related in 89% of the cases. In 47% of these IPF-related deaths, investigators characterized disease progression as acute or abrupt suggesting that an acute exacerbation of disease was the reason for death. Figure 1 illustrates the longitudinal change in FVC among the IPF patients who died abruptly (Panel A) and those that died due to sub-acute deterioration (Panel B). A decrease in FVC was not consistently noted in patients who died acutely. These data highlight limitations of physiological deterioration in predicting mortality and suggested that additional endpoints are needed to define longitudinal phenotype behavior in IPF. The occurrence of acute exacerbations in IPF is an appropriate event-based component of a marker for disease progression.

Bottom Line: Disparate physiological approaches have also been taken to identify patients at risk of mortality, with varying results.Finally, CpG DNA exacerbated fibrosis in an in vivo model initiated by the adoptive transfer of primary fibroblasts derived from patients who exhibited rapidly progressing fibrosis.Together, these data suggested that TLR9 activation via hypomethylated DNA might be an important mechanism in promoting fibrosis particularly in patients prone to rapidly progressing IPF.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, USA.

ABSTRACT
Novel approaches are needed to define subgroups of patients with Idiopathic pulmonary fibrosis (IPF) at risk for acute exacerbations and/or accelerated progression of this generally fatal disease. Progression of disease is an integral component of IPF with a median survival of 3 to 5 years. Conversely, a high degree of variability in disease progression has been reported among series. The characteristics of patients at risk of earlier death predominantly rely on baseline HRCT appearance, but this concept that has been challenged. Disparate physiological approaches have also been taken to identify patients at risk of mortality, with varying results. We hypothesized that the rapid decline in lung function in IPF may be a consequence of an abnormal host response to pathogen-associated molecular patterns (PAMPs), leading to aberrant activation in fibroblasts and fibrosis. Analysis of upper and lower lobe surgical lung biopsies (SLBs) indicated that TLR9, a hypomethylated CpG DNA receptor, is prominently expressed at the transcript and protein level, most notably in biopsies from rapidly progressive IPF patients. Surprisingly, fibroblasts appeared to be a major cellular source of TLR9 expression in IPF biopsies from this group of progressors. Further, CpG DNA promoted profibrotic cytokine and chemokine synthesis in isolated human IPF fibroblasts, most markedly again in cells from patients with the rapidly progressive IPF phenotype, in a TLR9-dependent manner. Finally, CpG DNA exacerbated fibrosis in an in vivo model initiated by the adoptive transfer of primary fibroblasts derived from patients who exhibited rapidly progressing fibrosis. Together, these data suggested that TLR9 activation via hypomethylated DNA might be an important mechanism in promoting fibrosis particularly in patients prone to rapidly progressing IPF.

No MeSH data available.


Related in: MedlinePlus