Dataset Information

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival.

ABSTRACT:

Background

Idiopathic pulmonary fibrosis (IPF) is associated with increased expression of cyclin-dependent kinase inhibitors such as p16 and p21, and subsequent induction of cell cycle arrest, cellular senescence, and pro-fibrotic gene expression. We sought to link p16-expression with a diagnosis of IPF or other fibrotic interstitial lung diseases (ILDs), radiographic pattern, senescent foci-specific gene expression, antifibrotic therapy response, and lung transplant (LTx)-free survival.

Methods

Eighty-six cases of fibrosing ILD were identified with surgical lung biopsy. Immunohistochemistry for p16 was performed on sections with the most active fibrosis. p16-positive foci (loose collection of p16-positive fibroblasts with overlying p16-positive epithelium) were identified on digital slides and quantified. Cases were scored as p16-low (≤ 2.1 foci per 100 mm²) or p16-high (> 2.1 foci per 100 mm²). Twenty-four areas including senescent foci, fibrotic and normal areas were characterized using in situ RNA expression analysis with digital spatial profiling (DSP) in selected cases.

Results

The presence of p16-positive foci was specific for the diagnosis of IPF, where 50% of cases expressed any level of p16 and 26% were p16-high. There was no relationship between radiographic pattern and p16 expression. However, there was increased expression of cyclin-dependent kinase inhibitors, collagens and matrix remodeling genes within p16-positive foci, and cases with high p16 expression had shorter LTx-free survival. On the other hand, antifibrotic therapy was significantly protective. DSP demonstrated that fibroblastic foci exhibit transcriptional features clearly distinct from that of normal-looking and even fibrotic areas.

Conclusions

We demonstrated the potential clinical applicability of a standardized quantification of p16-positive fibroblastic foci. This method identifies an IPF phenotype associated with foci-specific upregulation of senescence-associated and matrix remodeling gene expression. While these patients have reduced LTx-free survival, good response to antifibrotic therapies was observed in those who were treated.

SUBMITTER: Keow J

PROVIDER: S-EPMC9175499 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival.

Keow Jonathan J Cecchini Matthew J MJ Jayawardena Nathashi N Zompatori Maurizio M Joseph Mariamma G MG Mura Marco M

Respiratory research 20220607 1

<h4>Background</h4>Idiopathic pulmonary fibrosis (IPF) is associated with increased expression of cyclin-dependent kinase inhibitors such as p16 and p21, and subsequent induction of cell cycle arrest, cellular senescence, and pro-fibrotic gene expression. We sought to link p16-expression with a diagnosis of IPF or other fibrotic interstitial lung diseases (ILDs), radiographic pattern, senescent foci-specific gene expression, antifibrotic therapy response, and lung transplant (LTx)-free survival. ...[more]

PMID: 35672770

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Project description:BackgroundPirfenidone is the first antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis (IPF) and it is used in the treatment of other interstitial pneumonias, such as unclassifiable interstitial lung disease (ILD) and connective tissue-related ILD. This study examined the efficacy of pirfenidone in patients with IPF and fibrotic idiopathic non-specific interstitial pneumonia (f-iNSIP).MethodsIn a retrospective real-life study, 67 IPF and 24 f-iNSIP patients were enrolled and classified into a pirfenidone group and a non-antifibrotic group. The level of forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLco) at baseline, 6, 12 and 24 months were recorded. The level of KL-6 in serum was detected by chemiluminescence enzyme immunoassay (CLEIA). The prognosis and safety outcomes were collected from patients.ResultsIn IPF patients, pirfenidone decreased the mean change of FVC and DLco, and decreased the proportion of patients with a ⩾10% decline in FVC or a ⩾15% decline in DLco compared with the non-antifibrotic group. There was no difference in the mean change of FVC and DLco between smokers and non-smokers who received pirfenidone treatment. There was an improvement in progression-free survival, defined as the time to the first occurrence of acute exacerbation or death related to pulmonary fibrosis. Moreover, the ratio of patients who experienced acute exacerbation and death related to pulmonary fibrosis was lower in the pirfenidone group. There was no change in lung function and prognosis between the pirfenidone and non-antifibrotic groups in f-iNSIP patients. The KL-6 level slightly decreased after 1 year of pirfenidone treatment but not significantly. Gastrointestinal and skin-related adverse events were most common, and four patients ceased treatment due to the side effects.ConclusionsPirfenidone safely reduced disease progression by improving the lung function and progression-free survival in IPF patients, with acceptable side effects. The efficacy of pirfenidone on f-iNSIP was not significant, suggesting the need for further studies.The reviews of this paper are available via the supplemental material section.

Project description:BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is well known as a life-threatening condition during its clinical course. However, the clinical features and prognosis in AE of unclassifiable idiopathic interstitial pneumonia (AE-UCIIP) remain to be elucidated. The aim of this study was to clarify the clinical features and prognosis of AE-UCIIP compared with those of AE-IPF.MethodsIn 187 patients with UCIIP or IPF, 64 patients with AE-UCIIP or AE-IPF, who were diagnosed and treated at our hospital, were retrospectively evaluated.ResultsA total of 24 patients with AE-UCIIP were significantly older (p = 0.011), included more women (p < 0.001) and never-smokers (p < 0.001), and showed fewer lung lesions on high-resolution computed tomography (p = 0.006) than 40 patients with AE-IPF. Incidence of AE-UCIIP was 10.29%/year and was significantly higher than in AE-IPF (Gray's test, p = 0.008). Prognosis of AE-UCIIP was as poor as that of AE-IPF (log-rank, p = 0.681). Percent-predicted forced vital capacity (%FVC) [hazard ratio (HR) 0.934, p = 0.045], and GAP stage within 12 months before AE (HR 3.530, p = 0.023), and partial pressure arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio at AE (HR 0.998, p = 0.016) were significant prognostic factors. Finally, commencement of long-duration (⩾12 h) direct hemoperfusion with a polymyxin B-immobilised fibre column (PMX-DHP) within 2 days after admission significantly improved survival (log-rank, p = 0.038) and was a significant prognostic factor (HR 0.175, p = 0.0039) in AE-UCIIP. Long-duration PMX-DHP showed favourable treatment effects even in the combined group of patients with AE-UCIIP or AE-IPF (log-rank p = 0.002; HR 0.328, p = 0.006).ConclusionsPatients with AE-UCIIP were older and included more women and never-smokers than those with AE-IPF. Prognosis of AE-UCIIP was as poor as that of AE-IPF. The reviews of this paper are available via the supplemental material section.

Dataset Information

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival.

Background

Methods

Results

Conclusions

Publications

Digital quantification of p16-positive foci in fibrotic interstitial lung disease is associated with a phenotype of idiopathic pulmonary fibrosis with reduced survival.

Similar Datasets

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