Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes

Abstract

Purpose of Study: Studies of pulmonary fibrosis (PF) have resulted in DNA damage, inflammatory response, and cellular senescence, being widely hypothesized to play a role in the progression of the disease. Utilizing these aforementioned terms, genomics databases were interrogated along with the term, “pulmonary fibrosis,” to identify genes common among all 4 search terms. Findings were compared to data derived from a model of radiation-induced progressive pulmonary fibrosis (RIPF) to verify that these genes are similarly expressed, supporting the use of radiation as a model for diseases involving PF, such as human idiopathic pulmonary fibrosis (IPF). Materials and Methods: In an established model of RIPF, C57BL/6J mice were exposed to 12.5 Gy thorax irradiation and sacrificed at 24 hours, 1, 4, 12, and 32 weeks following exposure, and lung tissue was compared to age-matched controls by RNA sequencing. Results: Of 176 PF associated gene transcripts identified by database interrogation, 146 (>82%) were present in our experimental model, throughout the progression of RIPF. Analysis revealed that nearly 85% of PF gene transcripts were associated with at least 1 other search term. Furthermore, of 22 genes common to all four terms, 16 were present experimentally in RIPF. Conclusions: This illustrates the validity of RIPF as a model of progressive PF/IPF based on the numbers of transcripts reported in both literature and observed experimentally. Well characterized genes and proteins are implicated in this model, supporting the hypotheses that DNA damage, inflammatory response and cellular senescence are associated with the pathogenesis of PF.

Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis

“…TGF-β1 stimulates the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (protein kinase B) (PI3K/Akt), Rho, and MAPK. Radiation-induced fibrosis is characterized by an upregulation of TGF-β1 [ 21 , 23 , 84 , 105 , 106 ].…”

Greater Odds for Angina in Uranium Miners Than Nonuranium Miners in New Mexico

“…Radiation exposure has been studied extensively as a cause for pulmonary fibrosis, hematological disorders, and certain cancers (3)(4)(5)(6)(7). There is also a growing number of studies showing that high-dose ionizing radiation exposure in environmental and therapeutic settings increases the risk for cardiovascular diseases (8)(9)(10).…”

The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation

“…The simplest hypothesis may be that the driver of these responses is radiation-induced cell death associated with turnover of lethally damaged cells or senescence occurring in different organs at different times, leading to loss of stem/progenitor cells. However, a more comprehensive hypothesis would be that recognition of micronuclei (61,62), microbes or damage-associated immune responses (63,64) trigger further late damage expression through generating chronic inflammation.…”

“…Part of the response to radiation involves rapid mobilization of bone marrow-derived myeloid cells that act as first responders to danger (13,33). This triggers downstream common myeloid progenitors to replenish cells of the myeloid and erythroid system that ''die in action'' (62), that decrease GI-ARS (14,65,66) by forming stem cell niches (61) and that heal radiation-induced wound-healing defects (67). Perhaps chronic late life-shortening is the price that must be paid for acute life-saving myelopoiesis.…”