The Role of Transforming Growth Factor β in Lung Development and Disease

Gene expression studies were undertaken in normal pancreas and pancreatic adenocarcinomas to determine new candidate genes that can potentially be used as markers of the disease. The characteristic desmoplastic stromal reaction of pancreatic adenocarcinoma greatly hampers expression studies in this tumour type, and usually necessitates time-consuming tissue microdissection for enrichment of the tumour cell population. We show that fine needle aspiration of cancer provides a fast and efficient way of obtaining samples highly enriched in tumour cells with sufficient yields of RNA. Using Atlas cancer cDNA arrays with 588 cancer-related genes, we describe gene expression profiles of normal pancreas, bulk pancreatic tumour tissues and pancreatic tumour aspirates containing more than 95% tumour cells. Analysis of bulk tissue specimens revealed differentially expressed genes belonging predominantly to the stromal component of the tumour. This contrasted with the results obtained from tumour-cell enriched samples. Several genes already described in pancreatic cancer (caspase 8, TIMP1, CD9, IL-13) were also differentially expressed in our study. Furthermore, we found dysregulated expression of genes not previously associated with pancreatic adenocarcinoma, such as Rac 1, GLG1, NEDD5, RPL-13a, RPS9 and members of the Wnt5A gene family. In summary, we present a panel of genes newly identified in the pathogenesis of pancreatic adenocarcinoma and demonstrate that fine needle aspirates of the tumour mass are a convenient source of material for gene expression studies in tumours accompanied by desmoplastic reactions.

Gene expression profiles of pancreatic cancer and stromal desmoplasia.

Pulmonary fibrosis is a chronic progressive disease with no effective therapy. Transforming growth factor beta (TGF-beta) is thought to be a key profibrotic mediator and blocking its activity is therefore one of the targets of new treatment strategies for fibrosis. Decorin is an endogenous proteoglycan and one of the known inhibitors of TGF-beta. The short half-life of peptide-based therapeutics makes gene transfer a promising approach to achieve prolonged protein levels in the lung. Replication-deficient adenovirus was used to deliver decorin transgene (AdDec) to the airways by a single intranasal injection in a murine bleomycin model of lung fibrosis. The ability of vector-derived decorin to inhibit TGF-beta was examined in a bioassay and its effect on bleomycin-induced pulmonary fibrosis was determined by histomorphology and lung hydroxyproline. In vitro, supernatant from cells infected with AdDec abrogated the bioactivity of TGF-beta in a dose-dependent manner whereas control virus (AdDL70) had no effect. In vivo, treatment of bleomycin-injected mice with AdDec substantially reduced the fibrogenic response compared with control virus (hydroxyproline: bleomycin/AdDec, 1.96 microg/mg; bleomycin/AdDL70, 3.05 microg/mg; p = 0.0005). These results suggest that a single administration of AdDec was able to generate a local pulmonary environment that effectively blocked the fibrogenic response to bleomycin by inhibition of TGF-beta.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.163.3.2006084

Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin.

Summary
Background The amniotic membrane (AM), which is the innermost layer of the placenta, was shown to possess anti-inflammatory and anti-fibrotic properties in various in vitro and clinical studies.

Purpose To evaluate the anti-fibrotic and anti-inflammatory effects of the AM matrix (AMM) on human conjunctival and lung fibroblasts in an in vitro system that tests fibrotic and inflammatory responses at the effector stages of allergic inflammation.

Methods Human conjunctival or lung fibroblasts were seeded on plastic or on the stromal aspect of the AM, which was mounted on plastic inserts. Sonicates of human peripheral blood eosinophils activated with lipopolysacharide (LPS), or human mast cell (HMC-1) leukaemia cell sonicates, were added to sub-confluent fibroblast monolayers. Proliferation of the sub-confluent fibroblasts was assessed using the [3H]-thymidine incorporation assay. The production of transforming growth factor (TGF)-β1, granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-8 in conjunctival or lung fibroblasts was measured in conditioned media from these cultures by ELISA.

Results After 4 days in culture, the [3H]-thymidine incorporation assay indicated a reduced proliferation of activated conjunctival and lung fibroblasts when cultured directly on the AMM. The production of both TGF-β1 and IL-8 was significantly suppressed in activated conjunctival fibroblasts cultured on the AMM compared with those cultured on plastic, while the production of both TGF-β1 and GM-CSF was decreased in human lung fibroblast cultured on the AMM.

Conclusions The AMM is capable of suppressing fibrotic responses in an in vitro system of effector stages of ocular allergic inflammation. These data may provide a basis for exploring matrix components in the AM for the treatment of allergic eye disease.

Suppression of inflammatory and fibrotic responses in allergic inflammation by the amniotic membrane stromal matrix.

Background Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC. Methodology/principal findings In 52 NSCLC patients (stage I-III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-beta1, and immunoreactivity was quantified (grade 1-4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-beta1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-beta1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients. Conclusions/significance The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-beta1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC.

/pdf/cytokine-plasma-levels-reliable-predictors-for-radiation-4v5cxbg3qw.pdf

Cytokine plasma levels: reliable predictors for radiation pneumonitis?

Role of transforming growth factor-β1 and decorin in development of central fibrosis in pulmonary adenocarcinoma

Well-differentiated fetal adenocarcinoma of lung

A case of glycogen-rich clear cell carcinoma (GRCC) which arose in the right breast of a 35-year-old Japanese woman is reported. Light microscopic examination of the tumor revealed solid alveolar proliferation of clear cells containing abundant glycogen. Electron microscopy identified aggregates of glycogen particles and numerous empty glycogen lakes. This case is reported with a discussion on the other 42 GRCC cases reported in the international literature.

Glycogen-rich Clear Cell Carcinoma of the Breast: A Case Report and Review of the Literature.

Benign Endobronchial Lipoma: A Case Report and Review of the Literature

巨大肺嚢胞症の86嚢胞切除例に対し, 肺機能検査, 133Xeガスによる肺換気シンチグラムを中心に検討を加えた.術前の合併症としては, 気胸・呼吸不全・嚢胞内感染が多くみられ, 特に高齢者で合併症を伴ったものでは5例の術後死亡を認めた.巨大肺嚢胞症では, このような合併症の起こらない早期に外科治療を行い, 合併症の予防・肺機能の温存を計る必要がある.肺換気シンチグラムによる巨大肺嚢胞症の43例を非交通性嚢胞15例と交通性嚢胞28例とに分類すると, 非交通性嚢胞では術前に自覚症状があり, 肺機能低下例が多いため, 術後に有意の改善が得られた.術後に改善した肺機能は閉塞性障害の強い症例では次第に低下傾向があるものの, 長期間にわたり維持され, 外科治療は有意義であった.中・下葉に局在する巨大肺嚢胞は, 術前に肺機能の低下が著しく, 術後に有意の改善が得られた.

Evaluation of surgical therafpy for giant bullae

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