Gene Expression Profiling Distinguishes Radiation-Induced Fibrosing Alveolitis from Alveolitis in Mice

Combined Tlr2 and Tlr4 Deficiency Increases Radiation-Induced Pulmonary Fibrosis in Mice

“…The plausibility of a unique effect of combined Tlr2,4 mutations on T lymphocyte populations was recently demonstrated by Martin et al (39), who showed contact hypersensitivity, a T-cell-mediated inflammatory skin disease, to be abolished in Tlr2,4-/-but not Tlr4-/-mice. In addition, the enhanced lung disease in the Tlr2,4 knockout could involve altered Tlr signaling in B lymphocytes (40,41), a hypothesis supported by our gene expression data, which implicate B cell proliferation and the associated complement response as significant pathways in the radiation-induced pulmonary fibrosis response of B6 mice (18). Furthermore, as Tlr2 and Tlr4 receptors are also expressed on neutrophils (42), and as we have previously shown the numbers of lavage neutrophils to be positively correlated with fibrotic lung disease in a population of genetically mixed mice (8), it is conceivable that defective Tlr signaling in this cell type could affect the level of pulmonary fibrosis.…”

“…As the development of fibrotic lung disease can involve the excessive deposition of fibronectin (16) or can occur through mutations in surfactant protein A (17), it is possible that altered signaling through Tlrs may be a component of radiation-induced fibrotic lung disease. In support of this hypothesis, we recently used gene expression microarray analysis to document the pathways involved in radiation-induced alveolitis and fibrosis (18) and identified Tlr signaling to be a significant component of the pulmonary response. In addition, as Tlr2 and Tlr4 are expressed on cell types putatively involved in the radiation response, including epithelial cells that respond to tissue damage through cytokine secretion (19), defective Tlr2 and/or Tlr4 signaling could alter the tissue capacity to heal from radiationinduced injury.…”

“…Quantitative real-time polymerase chain reaction assays were performed using the Applied Biosystems International Prism 7500 Sequence Detection System using the TaqMan Gene expression assays Mm00477731_m1 for Hyal2 and Mm00515089_m1 for Has2. Ataxin 10 (Atxn10, Assay Mm00450332_m1) was used as the reference gene as in a prior study (18).…”

Combined CXCR1/CXCR2 Antagonism Decreases Radiation-Induced Alveolitis in the Mouse

“…Related to this, high neutrophil levels in bronchoalveolar lavage have also been reported to be a feature of idiopathic (6) and familial pulmonary fibrosis (7). Finally, supporting the observation of neutrophil recruitment in the pulmonary radiation response, radiation-induced changes in the pulmonary expression levels of particular chemokines and their receptors, which function in neutrophil recruitment and activation (8), such as Cxcl1 and Cxcr2 have been reported (9,10).…”

“…Lung damage was induced by whole-thorax irradiation (18 Gy; dose rate 0.6 Gy/min) using a Gammacell 137 Cs unit as described previously (5,9,(19)(20)(21)(22). The rest of the body was shielded with 3 cm of lead to reduce the beam strength to 3% in this area.…”