Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-β₁ has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-β₁ in the lung and its roles in the pathogenesis of these responses are not completely understood. In addition, the relationships between apoptosis and other TGF-β₁–induced responses have not been defined. To address these issues, we targeted bioactive TGF-β₁ to the murine lung using a novel externally regulatable, triple transgenic system. TGF-β₁ produced a transient wave of epithelial apoptosis that was followed by mononuclear-rich inflammation, tissue fibrosis, myofibroblast and myocyte hyperplasia, and septal rupture with honeycombing. Studies of these mice highlighted the reversibility of this fibrotic response. They also demonstrated that a null mutation of early growth response gene (Egr)-1 or caspase inhibition blocked TGF-β₁–induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-β₁–induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-β₁ in vivo and define the critical role of Egr-1 in the TGF-β₁ phenotype. They also demonstrate that Egr-1–mediated apoptosis is a prerequisite for TGF-β₁–induced fibrosis and remodeling.

Transforming growth factor (TGF)-β 1 is an important regulator of inflammation and fibrosis. TGF-β 1 is usually secreted as a biologically latent protein called latent TGF-β 1 (L-TGF-β 1). L-TGF-β 1 has no biologic effect unless L-TGF-β 1 is converted to its active form. Using a well-recognized model of lung injury induced by the antineoplastic antibiotic bleomycin (Blm), we demonstrated that 7 d after intratracheal Blm administration, total lung TGF-β was maximally increased. This induction was due to TGF-β 1 production by alveolar macrophages that, when explanted, generated increased quantities of L-TGF-β 1 complexed with the glycoprotein thrombospondin (TSP)-1. The TSP-1/L-TGF-β 1 complex was associated with CD36, a receptor for TSP-1. The association of TSP-1/L-TGF-β 1 to CD36 was critical for plasmin-mediated release of mature TGF-β 1. In this paper we show that, compared with administration of Blm by itself, when a synthetic peptide of CD36 between amino acids 93 and 110 is given concomitantly with Blm to rats, alveolar macrophages generate markedly less active TGF-β 1, the rats gain weight more rapidly, and there is less inflammation, collagen I and III, and fibronectin synthesis. These findings demonstrate a novel in vivo mechanism of activation of L-TGF-β 1 in lung injury and the importance of alveolar macrophage–derived active TGF-β 1 in the pathogenesis of pulmonary inflammation and fibrosis.

Quercetin is a flavonoid with anticancer properties. In this study, we examined the effects of quercetin on cell cycle, viability, and proliferation of cancer cells, either singly or in combination with the microtubule-targeting drugs taxol and nocodazole. Although quercetin induced cell death in a dose-dependent manner, 12.5–50 μM quercetin inhibited the activity of both taxol and nocodazole to induce G2/M arrest in various cell lines. Quercetin also partially restored drug-induced loss in viability of treated cells for up to 72 h. This antagonism of microtubule-targeting drugs was accompanied by a delay in cell cycle progression and inhibition of the buildup of cyclin-B1 at the microtubule organizing center of treated cells. However, quercetin did not inhibit the microtubule targeting of taxol or nocodazole. Despite the short-term protection of cells by quercetin, colony formation and clonogenicity of HCT116 cells were still suppressed by quercetin or quercetin-taxol combination. The status of cell adherence to growth matrix was critical in determining the sensitivity of HCT116 cells to quercetin. We conclude that although long-term exposure of cancer cells to quercetin may prevent cell proliferation and survival, the interference of quercetin with cell cycle progression diminishes the efficacy of microtubule-targeting drugs to arrest cells at G2/M.