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The transition from normal lung anatomy to minimal and established fibrosis in idiopathic pulmonary fibrosis (IPF).

ABSTRACT:

Background

The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition.

Methods

Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples.

Findings

The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis.

Interpretation

The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis.

SUBMITTER: Xu F

PROVIDER: S-EPMC8054143 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The transition from normal lung anatomy to minimal and established fibrosis is a well-established feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition. Methods: Pre-operative thoracic MDCT scans of patients with severe IPF (n=9) treated by lung transplantation were used to identify regions of minimal (n=27) and established fibrosis (n=27). Micro-CT, quantitative histology and next-generation sequencing (RNAseq) were used to compare 24 samples from donor controls to minimal and established fibrosis samples. Findings: The present results confirmed an earlier report showing that the transition from normal lung anatomy to minimal and established fibrosis was associated with a reduction in the numbers of terminal bronchioles. In addition, this study substantially extended those observations by showing the activation of TGFBI, TLRs, NFÃŽÂºB, TGFÃŽÂ² pathways, and T cell co-stimulatory genes, as well as the down-regulation of inhibitory immune checkpoint genes in IPF affected lung tissue. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming the non-encapsulated lymphoid follicles. Fibrosis pathways, mucin secretion, surfactant, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis. Interpretation: The transition from normal lung anatomy to minimal and established fibrosis is associated with the up-regulation of TGFBI, TLRs, NFÃŽÂºB, TGFÃŽÂ² pathways, cytokine storm-related genes, and the down-regulation of inhibitory immune checkpoint, surfactant genes as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events all contribute to the pathogenesis of IPF.

Project description:BackgroundThe aim of this study was to analyze the relative frequency, clinical characteristics, disease onset and progression in f-IPF vs. sporadic IPF (s-IPF).MethodsFamilial IPF index patients and their family members were recruited into the European IPF registry/biobank (eurIPFreg) at the Universities of Giessen and Marburg (UGMLC). Initially, we employed wide range criteria of f-IPF (e.g. relatives who presumably died of some kind of parenchymal lung disease). After narrowing down the search to occurrence of idiopathic interstitial pneumonia (IIP) in at least one first grade relative, 28 index patients were finally identified, prospectively interviewed and examined. Their family members were phenotyped with establishment of pedigree charts.ResultsWithin the 28 IPF families, overall 79 patients with f-IPF were identified. In the same observation period, 286 f-IIP and s-IIP patients were recruited into the eurIPFreg at our UGMLC sites, corresponding to a familial versus s-IPF of 9.8%. The both groups showed no difference in demographics (61 vs. 79% males), smoking history, and exposure to any environmental triggers known to cause lung fibrosis. The f-IPF group differed by an earlier age at the onset of the disease (55.4 vs. 63.2 years; p < 0.001). On average, the f-IPF patients presented a significantly milder extent of functional impairment at the time point of inclusion vs. the s-IPF group (FVC 75% pred. vs. FVC 62% pred., p = 0.011). In contrast, the decline in FVC was found to be faster in the f-IPF vs. the s-IPF group (4.94% decline in 6 months in f-IPF vs. 2.48% in s-IPF, p = 0.12). The average age of death in f-IPF group was 67 years vs. 71.8 years in s-IPF group (p = 0.059). The f-IIP group displayed diverse inheritance patterns, mostly autosomal-dominant with variable penetrance. In the f-IPF, the younger generations showed a tendency for earlier manifestation of IPF vs. the older generation (58 vs. 66 years, p = 0.013).ConclusionsThe 28 f-IPF index patients presented an earlier onset and more aggressive natural course of the disease. The disease seems to affect consecutive generations at a younger age.Trial registrationNr. NCT02951416 http://www.www.clinicaltrials.gov.

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