Effects of alpha 1-antitrypsin on endotoxin-induced lung inflammation in vivo

Department of Respiratory Medicine, Hannover Medical School, Germany.
Agents and Actions (Impact Factor: 2.35). 03/2010; 59(7):571-8. DOI: 10.1007/s00011-010-0164-x
Source: PubMed


Previous in vitro experiments demonstrated that acute-phase protein, alpha 1-antitrypsin (AAT), could act either as an enhancer or as a suppressor of lipopolysaccharide (LPS)-induced cell activation depending on treatment time. Here we investigate how AAT regulates inflammatory responses in the short term when administrated post LPS challenge.
Similar experimental setup was used both in vitro and in vivo: human monocytes and neutrophils were stimulated with LPS for 2 h followed by AAT for a total time of 4 h, and C57BL/6 mice were treated intranasally with LPS and 2 h later with AAT and sacrificed after 4 h. Bronchial lavage (BAL) and lung homogenates were analyzed using bio-plex cytokine assay. BAL cell counts were assessed.
Within 4 h, AAT enhanced LPS-induced tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, and IL-8 release from monocytes and neutrophils. Mice challenged for 4 h with LPS followed by AAT at 2 h showed no changes in BAL cell counts and higher levels of almost all measured cytokines, specifically RANTES in BAL and IL-12, IL-13, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-10 levels in lung homogenates, than in mice treated with LPS only.
Within the short term, AAT enhances the magnitude of LPS-induced specific cytokine/chemokine production, which may play an important role in amplification and resolution of acute-phase inflammatory reactions in vivo.

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    • "AAT has been shown to increase fibroblast proliferation, to inhibit neutrophil chemotaxis, superoxide production and cell apoptosis [18]. AAT specifically enhanced lPS induced RANTES expression in BAl and Il-10, Il-12 and Il-13 levels in lung homogenates [19]. All of this indicates that SERPINA1 plays an important regulatory role in various inflammatory cascades. "
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    ABSTRACT: BACKGROUND: The inflammatory process underlying nasal polyposis is induced and perpetuated by the enhanced activity of several agents including transcription factors. It has recently been demonstrated that one of them, named nuclear factor-kappa B (NF-κB), is implicated in the regulation of multiple pro-inflammatory genes. OBJECTIVES: The aim of the study was to identify using microarray technology which NF-κB-dependent genes are activated in nasal polyp (NP) samples compared to the control mucosa. MATERIAL AND METHODS: The transcriptional activity of genes was analyzed using an oligonucleotide microarray on 15 NPs and 8 cases of normal nasal mucosa. RESULTS: Gene expression patterns obtained in NPs were significantly different from those in normal mucosa. NPs and control cases clustered separately, each of them with large homogeneity in gene expression. Among 582 human NF-κB-dependent genes 25 showed a significantly higher expression in NPs compared to the control. The largest increase focused on gene encoding TFF3 (a 5-fold higher expression) followed by NOS2A (5x), SERPINA1 (4x), UCP2 (4x), OXTR (4x) and IL8 (3x) (p<0.05). In healthy mucosa 19 genes presented increased transcription activity compared to NPs. The most significantly enhanced levels were shown LTF gene (20 fold) followed by KRT6B (7x), LYZ (7x), SD11B2 (5x) and MMP3 (4x) (p<0.05). CONCLUSIONS: DNA microarray technology highlights the involvement of many unsuspected pathologic pathways which could be involved in NP growth. The identification of novel disease-related genes may help to understand the biology of NPs and elaborate new targeted therapy.
    Advances in Clinical and Experimental Medicine 03/2013; 22(2):209. · 1.10 Impact Factor
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    • "Similarly, in this study, A1AT was localised to the syncytiotrophoblasts and the endothelial cells. Pro-inflammatory cytokines TNFa and interleukin 6 induce A1AT in human amnion (Izumi-Yoneda et al. 2009) and A1AT enhances the magnitude of LPS-induced specific cytokine/chemokine production (Subramaniyam et al. 2010) via the transcription factors NF-kB and AP-1 (Dichtl et al. 2000), which may play an important role in amplification of acute-phase inflammatory reactions. ANXA5 has anti-inflammatory, anti-thrombotic and anti-apoptotic properties (Leon et al. 2006, Ewing et al. 2011). "
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    ABSTRACT: Our aim was to study the protein expression profiles of placenta obtained from lean and obese pregnant women with normal glucose tolerance at the time of term Caesarean section. We used two-dimensional difference gel electrophoresis (2D-DIGE), utilising narrow-range immobilised pH gradient strips that encompassed the broad pH range of 4-5 and 5-6, followed by MALDI-TOF mass spectrometry of selected protein spots. Western blot and quantitative RT-PCR (qRT-PCR) analyses were performed to validate representative findings from the 2D-DIGE analysis. Eight proteins were altered (six down-regulated and two up-regulated on obese placentas). Annexin A5 (ANXA5), ATP synthase subunit beta, mitochondria (ATPB), brain acid soluble protein 1 (BASP1), ferritin light chain (FTL), heterogeneous nuclear ribonucleoprotein C (HNRPC) and vimentin (VIME) were all lower in obese patients. Alpha-1-antitrypsin (A1AT) and stress-70 protein, mitochondrial (GRP75) were higher in obese patients. Western blot analysis of ANXA5, ATPB, FTL, VIME, A1AT and GRP75 confirmed the findings from the 2D-DIGE analysis. For brain acid soluble protein 1 and HNRPC, qRT-PCR analysis also confirmed the findings from the 2D-DIGE analysis. Immunohistochemical analysis was also used to determine the localisation of the proteins in human placenta. In conclusion, proteomic analysis of placenta reveals differential expression of several proteins in patients with pre-existing obesity. These proteins are implicated in a variety of cellular functions such as regulation of growth, cytoskeletal structure, oxidative stress, inflammation, coagulation and apoptosis. These disturbances may have significant implications for fetal growth and development.
    Journal of Molecular Endocrinology 02/2012; 48(2):139-49. DOI:10.1530/JME-11-0123 · 3.08 Impact Factor
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