Effects of alpha 1-antitrypsin on endotoxin-induced lung inflammation in vivo.
ABSTRACT 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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ABSTRACT: One would assume that the anti-inflammatory activity of α1-antitrypsin (AAT) is the result of inhibiting neutrophil enzymes. Yet, AAT exhibits tolerogenic activities that are difficult to explain by serine-protease inhibition, nor by reduced inflammatory parameters. Targets outside the serine-protease family have been identified, supporting the notion that elastase inhibition, the only functional factory release criteria for clinical-grade AAT, is overemphasized. Non-obvious developments in the understanding of AAT biology disqualify it from being a straightforward anti-inflammatory agent: AAT does not block dendritic cell activities, nor does it promote viral and tumor susceptibilities, stunt B-lymphocyte responses or render treated patients susceptible to infections; accordingly, outcomes of elevated AAT do not overlap those attained by immunosuppression. Aside from the acute phase response, AAT rises during the third trimester of pregnancy and also in advanced age. At the molecular level, AAT docks onto cholesterol-rich lipid-rafts and circulating lipid particles, directly binds IL-8, ADAM17 and danger-associated molecular pattern (DAMP) molecules, and its activity is lost to smoke, high glucose levels and bacterial proteases, introducing a novel entity – ‘relative AAT deficiency’. Unlike immunosuppression, AAT appears to help the immune system distinguish between desired responses against authentic threats, and unwanted responses fueled by a positive feedback loop perpetuated by, and at the expense of, inflamed injured innocent bystander cells. With a remarkable clinical safety record, AAT treatment is currently tested in clinical trials for its potential benefit in a variety of categorically distinct pathologies that share at least one common driving force – cell injury.Clinical & Experimental Immunology 10/2014; 179(2). DOI:10.1111/cei.12476 · 3.28 Impact Factor
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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.22(2):209.
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ABSTRACT: Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.Biological research 10/2014; 2014, 47:58(47):58. DOI:10.1186/0717-6287-47-58 · 1.04 Impact Factor