Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis

Resistance to bleomycin increases the chronological life of cells

The identification of genes involved in chronological aging could have a potential utility as molecular markers in the chemotherapy treatment of cancer. The aim of this work is to study the relationship between the chronological aging and the resistance to Bleomycin for the purpose of establish the basic interactions between these phenomenons for further investigation of molecular markers.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Cisplatin-based chemotherapy of testicular cancer - Two decades after a major breakthrough

Two decades ago the introduction of cisplatin-based combination chemotherapy has dramatically improved the prognosis of patients with metastatic testicular cancer, At present 3 cycles of cisplatin, etoposide and bleomycin are considered as standard treatment for good-risk metastatic disease. Outside of clinical trials patients in the intermediate and poor prognosis categories should receive 4 cycles of this standard regimen, Clinical trials currently evaluate the role of high-dose chemotherapy in first-line treatment of high-risk patients and in the salvage setting, Post-chemotherapy resection of tumor residuals remains an important part of therapy. Attention should be focused on long-term toxicity of therapy and the occurrence of late relapse

Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

PMCID: PMC3212807This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Efficacy of Combined 5-Fluorouracil and Photodynamic Therapy in Glioma Spheroids

Standard treatment regimens consisting of surgery, radiation and chemotherapy have proven ineffective for the treatment of high-grade gliomas such as glioblastoma multiforme (GBM). An effective cure requires elimination of nests of tumor cells that have migrated from the resection margin and infiltrated normal brain. A number of localized therapies, including light-based approaches such as photodynamic therapy (PDT) and photochemical internalization (PCI) are currently under investigation for the management of GBM patients. Several studies have demonstrated a high degree of synergy between PDT and bleomycin, via the PCI mechanism, in a variety of in vitro and in vivo models, including glioma cell lines. The purpose of this study was to examine the efficacy of combined treatments consisting of PDT and the chemotherapeutic agent, 5-fluorouracil (5-FU) in a 3-dimensional spheroid model consisting of F98 rat glioma cells. Spheroids were incubated with a photosensitizer (aluminum phthalocyanine disulfonate; AlPcS2a) and irradiated with 670 nm laser light. Three different wash protocols (0, 4 and 24 h) were employed to determine whether any observed interactions between PDT and 5-FU could be attributed to the PCI mechanism, or were simply due to different cytotoxic pathways of the two treatment modalities. Although the combined PDT + 5-FU treatments resulted in greater suppression of spheroid growth compared to either treatment alone, no statistically significant differences in growth effects were observed between 0 and 4 h wash protocols suggesting that the combined treatment effects were due to different mechanisms of cytotoxicity, rather than a PCI effect

Increased expression of 5-hydroxytryptamine(2A/B) receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention

Background Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR2A and 5-HTR2B receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR2A/B signalling on lung fibrosis in vivo and in vitro. Methods and results Quantitative RT-PCR showed that the expression of 5-HTR1A/B and 5-HTR2B was significantly increased in the lungs of patients with IPF (n = 12) and in those with non-specific interstitial pneumonia (NSIP, n = 6) compared with transplant donors (n = 12). The expression of 5-HTR2A was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR2A protein largely localised to fibroblasts, 5-HTR2B localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR2A/B antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor beta(1)- or WNT3a-induced collagen production. Conclusion The studies revealed an increased expression of 5-HTR2A specifically in IPF. Blockade of 5-HTR2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF

Amelioration of bleomycin-induced lung fibrosis in hamsters by dietary supplementation with taurine and niacin: biochemical mechanisms.

Interstitial pulmonary fibrosis induced by intratracheal instillation of bleomycin (BL) involves an excess production of reactive oxygen species, unavailability of adequate levels of NAD and ATP to repair the injured pulmonary epithelium, and an overexuberant lung collagen reactivity followed by deposition of highly cross-linked mature collagen fibrils resistant to enzymatic degradation. In the present study, we have demonstrated that dietary supplementation with taurine and niacin offered almost complete protection against the lung fibrosis in a multidose BL hamster model. The mechanisms for the protective effect of taurine and niacin are multifaceted. These include the ability of taurine to scavenge HOCl and stabilize the biomembrane; niacin's ability to replenish the BL-induced depletion of NAD and ATP; and the combined effect of taurine and niacin to suppress all aspects of BL-induced increases in the lung collagen reactivity, a hallmark of interstitial pulmonary fibrosis. It was concluded from the data presented at this Conference that the combined treatment with taurine and niacin, which offers a multipronged approach, will have great therapeutic potential in the intervention of the development of chemically induced interstitial lung fibrosis in animals and humans

Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation.

Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI-based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy