The transition from normal lung anatomy to minimal and established fibrosis in Idiopathic Pulmonary Fibrosis

ABSTRACT: 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, NFκB, TGFβ 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, NFκB, TGFβ 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.

PROVIDER: EGAS00001004758 | EGA |

REPOSITORIES: EGA