RATIONALE: Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury. OBJECTIVES: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-kappaB and AP-1 in lung fibrosis. METHODS: The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis. MEASUREMENTS AND MAIN RESULTS: Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-kappaB-driven cytokine expression in CD4(+) and CD8(+) T cells. CONCLUSIONS: These results suggest that the specific inhibition of NF-kappaB could be useful for the treatment of lung fibrosis.
RATIONALE: Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury. OBJECTIVES: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-kappaB and AP-1 in lung fibrosis. METHODS: The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis. MEASUREMENTS AND MAIN RESULTS: Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-kappaB-driven cytokine expression in CD4(+) and CD8(+) T cells. CONCLUSIONS: These results suggest that the specific inhibition of NF-kappaB could be useful for the treatment of lung fibrosis.
Authors: Alexander N Garcia; Nancy G Casanova; Carrie L Kempf; Tadeo Bermudez; Daniel G Valera; Jin H Song; Xiaoguang Sun; Hua Cai; Liliana Moreno-Vinasco; Taylor Gregory; Radu C Oita; Vivian Reyes Hernon; Sara M Camp; Claude Rogers; Espoir M Kyubwa; Naresh Menon; James Axtelle; Jay Rappaport; Christian Bime; Saad Sammani; Anne E Cress; Joe G N Garcia Journal: Am J Respir Cell Mol Biol Date: 2022-05 Impact factor: 7.748
Authors: Hagir B Suliman; Zachary Healy; Fabio Zobi; Bryan D Kraft; Karen Welty-Wolf; Joshua Smith; Christina Barkauskas; Claude A Piantadosi Journal: iScience Date: 2021-12-01
Authors: Zhenguo Zeng; Weiguo Chen; Alexander Moshensky; Zaid Shakir; Raheel Khan; Laura E Crotty Alexander; Lorraine B Ware; C M Aldaz; Jeffrey R Jacobson; Steven M Dudek; Viswanathan Natarajan; Roberto F Machado; Sunit Singla Journal: Am J Respir Cell Mol Biol Date: 2021-01 Impact factor: 6.914