Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

Abstract

-Although paraquat (PQ) is widely known to induce pulmonary fibrosis, the molecular mechanisms are poorly understood. Therefore, to bring a new dimension to the elucidation of the mechanisms, we conducted microarray experiments to investigate the expression profiles of 1,090 genes in the lungs during the progressive phase of PQ-induced pulmonary fibrosis in rats. After several s.c. injections of PQ, rats were divided into a fibrogenic group and a non-fibrogenic group. Time-course gene expression analysis of the fibrogenic group showed altered gene regulation throughout the experimental period. The expression levels of many cell membrane channel, transporter, and receptor genes were substantially altered. These genes were classified into two categories: polyamine transporter-and electrolyte/fluid balance-related genes. Moreover, comparative analysis of the fibrogenic and the non-fibrogenic group revealed 36 genes with significantly different patterns of expression, including the pro-apoptotic gene Bad. This indicates that Bad is a key factor in apoptosis and that apoptosis provides a major turning point in PQ-induced pulmonary fibrosis. Notably, subtypes of transforming growth factor (TGF)-β genes that are considered to play a pivotal role in fibrogenesis showed no differences in expression between the two groups, though TGF-β3 was markedly induced in both groups. These results provide novel and extensive insights into the molecular mechanisms that lead to pulmonary fibrosis after exposure to PQ.

The role of Bcl-2 family proteins in pulmonary fibrosis

“…Increased levels of Bcl-2 and Bcl-xL in the alveolar macrophages surviving under the exposure to low doses of asbestos and production of TGF-beta1 by these cells have been also observed in asbestos model of lung fibrosis (Nishimura et al, 2007). Altered expression of pro-apoptotic gene Bad has been implicated as an important factor in paraquat-induced pulmonary apoptosis and fibrosis which was associated with markedly increased expression of TGFbeta3 (Satomi et al, 2007).…”

PSTK is a novel gene associated with early lung injury in Paraquat Poisoning

“…Clues for early diagnosis might come from the identification of genes tied to the early stage of PQ development. Previously, the Illumina gene chip has been used to define the PQ-induced gene changes in the brain and lung [6][7][8] (however, that report was based upon the use of PCR and cDNA technology and the number of genes examined was limited to around 1000) while current technology allows the use of high-throughput gene chips to explore the genetic changes on a genome wide scale [9][10][11]. In our study we used the Affymetrix Rat Gene1.0 mouse gene chip; this method allows for more than 27,000 genes to be examined, and provides higher sensitivity and comprehensiveness as compared with the previous tools [12].…”

Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro

“…Many papers concerning the drug-induced lung fibrosis animal models have been reported to date (Adamson, 1976;Satomi et al, 2007;Moeller et al, 2008;Lacerda et al, 2009). Fleischman et al (1971) and McCullough et al (1978) have reported that treatment with BLM resulted in the induction of lung fibrosis in canines and baboons, and BLM induced diffuse alveolar injury and subsequent pulmonary fibrosis (Blum et al, 1973;Rabinowits et al, 1990).…”