Immunohistochemical Localization of Transforming Growth Factor β and Tumor Necrosis Factor α in the Lungs of Fibrosis-Prone and "Non-Fibrosing" Mice during the Latent Period and Early Phase after Irradiation

Abstract

To evaluate the possibility that TGF-beta and TNF-alpha are involved in fibrosis induced in mouse lung by irradiation, the proportion of cells immunoreactive for each was compared in two strains of mice. C3HeB/FeJ mice develop only classical pneumonitis during the early phase, whereas C57L/J mice develop small, tightly packed areas of inflammation which undergo fibrosis during the latent period, and exhibit progressive fibrosis of large regions of intense inflammation during the early phase. Very few cells were immunoreactive for an antibody to the latency-associated peptide (LAP) of TGF-beta during the latent period in C3HeB/FeJ mice, and no cells were positive during the early phase. In contrast, between 0.7 and 10% of cells were positive in C57L/J mice in lesions without fibrosis and in lesions in the early stages of fibrosis. Fibroblasts positive for LAP were seen only in lesions containing fibrosis. A similar pattern of immunoreactivity was seen in C57L/J mice using an antibody which recognizes active TGF-beta, with the exception that positive fibroblasts were observed within areas of inflammation without fibrosis. Thus the association of active TGF-beta with fibroblasts might be a characteristic of the initiation of fibrosis in this model. TNF-alpha was detected in macrophages in all classes of lesions, and minor differences between the strains did not appear to be biologically meaningful.

Cytokine Polymorphisms and Histologic Expression in Autopsy Studies: Contribution of TNF-α and TGF-β1 to the Pathogenesis of Autoimmune-Associated Congenital Heart Block

“…The polymorphisms at positions ϩ869 and ϩ915, which change codon 10 (T or C, leucine3proline) and codon 25 (G or C, arginine3proline), respectively, are associated with interindividual variation in the levels of TGF-␤ production. This has clinical relevance because several animal and human studies have shown that high TGF-␤ producers develop significantly more lung fibrosis in response to a number of inflammatory triggers such as radiation (31), chemotherapy (32), and lung transplantation (33). For codon 25, the C allele encoding proline for these polymorphisms is associated with lower TGF-␤ synthesis in vitro and in vivo.…”

Ativação da proteína TGFbetaI latente em pulmão irradiado in vivo

“…Em culturas de fibroblastos e pneumócitos, a irradiação induziu a síntese de TGFβ1 nestas células 36 . Estudos in vivo, em pulmões de camundongos irradiados, mostraram a imunoexpressão da proteína TGFβ1 ativa em fibroblastos próximos à regiões que apresentavam lesões fibróticas 37 e em pneumócitos tipo II 4 . No entanto, estes trabalhos não estudaram especificamente a ativação in situ da proteína TGFβ1 em pulmão.…”

High superoxide dismutase and low glutathione peroxidase activities in red blood cells predict susceptibility of lung cancer patients to radiation pneumonitis

“…Late fibrosis might also develop months to years post-therapy. A possible contribution of cytokines and chemokines to the development of radiation-induced lung injury has been suggested [6][7][8][9][10]. The risk of radiation pneumonitis could also be strongly affected by various endogenous (genotypic) and exogenous (environmental) factors which vary among individuals [11].…”