Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Lunardi, Francesca; Villano, Gianmarco; Perissinotto, Egle; Agostini, Carlo; Rea, Federico; Gnoato, Marianna; Bradaschia, Alice; Valente, Marialuisa; Pontisso, Patrizia; Calabrese, Fiorella

doi:10.1038/labinvest.2011.1

Cited by 35 publications

(47 citation statements)

References 34 publications

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“…Idiopathic pulmonary fibrosis (IPF) lung samples wherein more extensive fibrosis was observed in patients with higher SERPINB3/B4 expression (Calabrese et al, 2008). Furthermore, it has confirmed that SERPINB3 plays role in inhibiting inflammation and favoring epithelial proliferation with increased TGF-β secretion and thus the likelihood of consequent fibrogenesis (Lunardi et al, 2011). DKK1, a secreted protein, controls Wnt signaling by binding the lung resistance-associated protein coreceptor and sterically blocking Wnt binding to the receptor complex (Bafico et al, 2001;Mao et al, 2001).…”

Section: Discussionmentioning

confidence: 95%

Luciferase Assay to Screen Tumour-specific Promoters in Lung Cancer

Guo²,

Xin³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Objective: Specific promoters could improve efficiency and ensure the safety of gene therapy. The aim of our study was to screen examples for lung cancer. Methods: The firefly luciferase gene was used as a reporter, and promoters based on serum markers of lung cancer were cloned. The activity and specificity of seven promoters, comprising CEACAM5 (carcinoembryonic antigen, CEA), GRP (Gastrin-Releasing Peptide), KRT19 (cytokeratin 19, KRT), SFTPB (surfactant protein B, SP-B), SERPINB3 (Squamous Cell Carcinoma Antigen, SCCA), SELP (Selectin P, Granule Membrane Protein 140kDa, Antigen CD62, GMP) and DKK1 (Dickkopf-1) promoters were compared in lung cancer cells to obtain cancer-specific examples with strong activity. Results: The CEACAM5, DKK1, GRP, SELP, KRT19, SERPINB3 and SFTPB promoters were cloned. Furthermore, we successfully constructed recombinant vector pGL-CEACAM5 (DKK1, GRP, SELP, KRT19, SERPINB3 and SFTPB) contained the target gene. After cells were transfectedwith recombinant plasmids, we found that the order of promoter activity from high to low was SERPINB3, DKK1, SFTPB, KRT19, CEACAM5, SELP and GRP and the order for promoters regarding specificity and high potential were SERPINB3, DKK1, SELP, SFTPB, CEACAM5, KRT19 and GRP. Conclusion: The approach adopted is feasible to screen for new tumour specific promoters with biomarkers. In addition, the screened lung-specific promoters might have potential for use in lung cancer targeted gene therapy research.

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Section: Discussionmentioning

confidence: 95%

Luciferase Assay to Screen Tumour-specific Promoters in Lung Cancer

Guo²,

Xin³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…SerpinB3 inhibits several types of proteases and plays a role in modulating inflammation, programmed cell death and fibrosis [27]. S100A8 and S100A9 proteins, so called calgranulins, are known for their antimicrobial activity and their role as pro-inflammatory mediators in acute and chronic inflammation [28]–[30].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, SerpinB3 and Uteroglobin decreased exclusively in young non-susceptible individuals, and ELISA experiments confirmed this for SerpinB3. The differential SerpinB3 and Uteroglobin response on smoking between the two young groups suggests that these proteins might be crucial for the very first steps towards COPD, given its modulatory function in inflammation and fibrosis [27] and release of lysosomal proteinases from damaged epithelial cells [34]. SerpinB3 concentrations have been shown to be higher in bronchoalveolar lavage fluid of smokers than non-smokers [35].…”

Section: Discussionmentioning

confidence: 99%

Susceptibility to COPD: Differential Proteomic Profiling after Acute Smoking

et al. 2014

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Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease), yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as “susceptible individuals”. Here we perform unbiased analyses of proteomic profiles to assess how “susceptible individuals” differ from age-matched “non-susceptible individuals” in response to cigarette smoking. Epithelial lining fluid (ELF) was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ) in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non-susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1) decreased both in young susceptible and non-susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying mechanisms that induce COPD. Our data suggest that SerpinB3 and Uteroglobin could be interesting proteins in understanding the processes leading to COPD.

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“…24 By immunohistochemistry SERPINB3 protein was documented in transgenic animals in the hepatocytes in the liver (Please see Supplementary Figure S1 available online at http://ebm.rsmjournals.com/ lookup/suppl/doi:10.1258/ebm.2012.012135/-/DC1), while in the lung it was mainly detected in the cytoplasm of inflammatory cells (mainly macrophages). 25 Mice were maintained under a 12 h light/dark cycle at 218C + 18C and bred at the Animal Care Facility of the Experimental Surgery Division of the University of Padua. In preliminary experiments, to assess the optimal dose to induce ALF, a group of 10 mice (5 transgenic and 5 wildtype) were inoculated intraperitoneally with increasing concentrations of acetaminophen and a concentration of 0.8 mg/g body weight was chosen for further experiments.…”

Section: Methodsmentioning

confidence: 99%

Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure

Villano

Lunardi

Turato

et al. 2012

Exp Biol Med (Maywood)

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Acute liver failure (ALF) is characterized by severe neurological complications, known as acute hepatic encephalopathy, where brain ammonia and inflammatory processes play a dominant role. In experimental models of acute liver failure SERPINB3 was found significantly increased in microglia, the intrinsic immune cells of the central nervous system. The aim of the present study was to investigate the extent of brain tissue damage and the inflammatory milieu in experimental acute liver failure using a SERPINB3-transgenic mouse model. C57BL/6J wild-type and transgenic mice were inoculated with acetaminophen or phosphate-buffered saline and sacrificed 20 h postinjection. Proliferation and apoptotic activity were analyzed in brain tissue by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique. The expression of cytokines was analysed in brain and liver tissue by real time polymerase chain reaction and in the corresponding serum samples using a Bio-Plex system. Acetaminophen induced a significantly lower body temperature and shorter survival in transgenic than in wild-type mice, despite liver function was similar in both groups. The brain of transgenic mice, expressing SERPINB3 positivity in microglia, showed increased glial cell number, associated to significant lower apoptotic death events, compared with wild-type mice. In mice injected with acetaminophen, remarkably higher values of cytokines mRNA were observed in the liver of both groups, with a trend toward higher values in transgenic animals. In brain tissue similar increase of tumor necrosis factor-α was detected in transgenic and wild-type mice, while IL-10 mRNA increased only in the wild-type group. A remarkable increase of circulating Th1 cytokines was detected in serum of transgenic mice, while in the wild-type group they remained rather unchanged. These figures were associated with lower levels of granulocyte macropage colony-stimulating factor, despite similar increase of IL-10 values in both groups. In conclusion, in acute liver failure SERPINB3 determines an enhanced inflammatory background, mainly mediated by higher levels of Th1 proinflammatory cytokines.

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Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice

Cited by 35 publications

References 34 publications

Luciferase Assay to Screen Tumour-specific Promoters in Lung Cancer

Luciferase Assay to Screen Tumour-specific Promoters in Lung Cancer

Susceptibility to COPD: Differential Proteomic Profiling after Acute Smoking

Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure

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