Activation of Oncogenic Pathways in Idiopathic Pulmonary Fibrosis

Stella, Giulia Maria; Inghilleri, Simona; Pignochino, Ymera; Zorzetto, Michele; Oggionni, Tiberio; Morbini, Patrizia; Luisetti, Maurizio

doi:10.1016/j.tranon.2014.05.002

Cited by 20 publications

(17 citation statements)

References 35 publications

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“…We have no explanation for the resemblance of the lung tissue microbial population between IPF and lung cancer patients. However, it is worth noting here that common genetic and epigenetic aberrations have been also reported in both IPF and lung cancer patients ( Vancheri et al, 2010 ; Vancheri, 2013 ; Vancheri and du Bois, 2013 ; Stella et al, 2014 ; Vancheri, 2015 ).…”

Section: Discussionmentioning

confidence: 71%

Identification of Halophilic Microbes in Lung Fibrotic Tissue by Oligotyping

et al. 2018

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Idiopathic pulmonary fibrosis (IPF) is an incurable disease with poor prognosis and unknown etiology. The poor clinical outcome is associated with enhanced microbial burden in bronchoalveolar lavage fluid from IPF patients. However, whether microbes from the respiratory tract fluid cause the disease remains uncertain. Tissue-associated microbes can influence host physiology in health and disease development. The aim of this study was to evaluate the existence of microbes in lung fibrotic tissues. We evaluated the microbial community in lung tissues from IPF and from human transforming growth factor-β1 (TGF-β1) transgenic mice with lung fibrosis by oligotyping. We also evaluated the microbial population in non-tumor-bearing tissues from surgical specimens of lung cancer patients. The phyla Firmicutes and the genus Clostridium tended to be predominant in the lung tissue from IPF and lung cancer patients. Oligotyping analysis revealed a predominance of bacteria belonging to the genera Halomonas, Shewanella, Christensenella, and Clostridium in lung tissue from IPF and lung cancer. Evaluation of the microbial community in the lung tissue from mice revealed abundance of Proteobacteria in both wild-type (WT) littermates and transgenic mice. However, the genus Halomonas tended to be more abundant in TGF-β1 transgenic mice compared to WT mice. In conclusion, this study describes tissue-associated microbes in lung fibrotic tissues from IPF patients and from aging TGF-β1 transgenic mice.

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Section: Discussionmentioning

confidence: 71%

Identification of Halophilic Microbes in Lung Fibrotic Tissue by Oligotyping

et al. 2018

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“…Control fibroblasts were stimulated for 30 minutes with 0 to 10 nM matriptase or for 0 to 60 minutes with 1 nM matriptase. We analyzed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and v-akt murine thymoma viral oncogene (AKT), which mediate influential signaling pathways in pulmonary fibrogenesis (25). Figure 3A shows that matriptase stimulated a time-and dosedependent phosphorylation of both kinases.…”

Section: Matriptase Evokes Fibroproliferative Responses In Vitro Viamentioning

confidence: 99%

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

Bardou

Menou

François

et al. 2016

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies.Objectives: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis.Methods: Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptaseinduced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings.Measurements and Main Results: Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-b. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic downregulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling.Conclusions: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF.

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“…Enrolment might be limited to this population, or the trial might use this cohort as a pre-specified target subgroup for which there is stratified randomisation [32]. As described for early phase proof of concept studies, cohort enrichment may also provide an opportunity for "predictive" cohort enrichment in later phase clinical trials by identifying subgroups of patients more likely to respond to a given drug [33,34]. This could be useful for treatments targeting specific sub-phenotypes of IPF, such as those with concomitant emphysema (so-called combined pulmonary fibrosis and emphysema) or pulmonary hypertension.…”

Section: Adaptation Of Late Phase Efficacy Trial Designs To the Emergmentioning

confidence: 99%

A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials

et al. 2015

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The past decade has seen substantial progress in understanding the pathobiology, natural history, and clinical significance of idiopathic pulmonary fibrosis (IPF), culminating in the establishment of two effective medical therapies. Now seems an important time to reconsider the design and conduct of future IPF clinical trials. Building on lessons learned over the past decade, we use this perspective to lay out four key considerations for moving forward effectively and efficiently with the next generation of clinical trials in IPF. These are: development of a coordinated IPF clinical trials network; establishment of expectations for early phase proof of concept studies; adaptation of late-phase efficacy trial designs to the emergence of approved therapies, and; agreement on primary end-points for late phase clinical trials. Continued progress in the field of IPF will require creativity and collaboration on the part of all stakeholders. We believe that addressing these four considerations will encourage and enable investment in this new era of drug development in IPF, and will lead to more rapid development of effective therapies. @ERSpublications What are the key considerations for the next generation of clinical trials in idiopathic pulmonary fibrosis? http://ow.ly/I0TUc

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Activation of Oncogenic Pathways in Idiopathic Pulmonary Fibrosis

Cited by 20 publications

References 35 publications

Identification of Halophilic Microbes in Lung Fibrotic Tissue by Oligotyping

Identification of Halophilic Microbes in Lung Fibrotic Tissue by Oligotyping

Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials

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