https://ogma.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38039 Wed 28 Jul 2021 09:42:45 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:11267 Wed 24 Jul 2013 22:28:44 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22098 Wed 19 Apr 2023 16:41:23 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47060 Wed 13 Mar 2024 08:04:20 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14161 Wed 11 Apr 2018 16:03:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14160 -/-), 4^-/- or 2/4^-/- BALB/c mice. Wt mice had moderate disease and infection. TLR2^-/- mice had more severe disease and more intense and prolonged infection compared to other groups. TLR4^-/- mice were asymptomatic. TLR2/4^-/- mice had severe early disease and persistent infection, which resolved thereafter consistent with the absence of symptoms in TLR4^-/- mice. Wt mice mounted robust innate and adaptive responses with an influx of natural killer (NK) cells, neutrophils, myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells, and activated CD4⁺ and CD8⁺ T-cells into the lungs. Wt mice also had effective production of interferon (IFN)c in the lymph nodes and lung, and proliferation of lymph node T-cells. TLR2^-/- mice had more intense and persistent innate (particularly neutrophil) and adaptive cell responses and IL-17 expression in the lung, however IFNγ responses and T-cell proliferation were reduced. TLR2/4^-/- mice had reduced innate and adaptive responses. Most importantly, neutrophil phagocytosis was impaired in the absence of TLR2. Thus, TLR2 expression, particularly on neutrophils, is required for effective control of Chlamydia respiratory infection in early life. Loss of control of infection leads to enhanced but ineffective TLR4-mediated inflammatory responses that prolong disease symptoms. This indicates that TLR2 agonists may be beneficial in the treatment of early life Chlamydia infections and associated diseases.]]> Wed 11 Apr 2018 13:47:06 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30208 Wed 11 Apr 2018 11:33:34 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40215 Wed 06 Jul 2022 16:26:34 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38106 Wed 04 Aug 2021 09:52:31 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:31006 Wed 02 Mar 2022 14:28:48 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33081 -/-) mice, one with a targeted deletion and another mutant expressing an major histocompatibility complex (MHC) transgene. To determine the importance of RelB in DCs, RelB-sufficient DCs (RelB^-/- or RelB^-/-) were adoptively transferred into RelB^-/- mice. Both strains had increased pulmonary inflammation compared to their respective wild-type (RelB^-/-) and heterozygous (RelB^-/-) controls. RelB^-/- mice also had increased inflammatory cell influx into the airways, levels of chemokines (CCL2/3/4/5/11/17, CXCL9/10/13) and Th2-associated cytokines (IL-4/5) in lung tissues, serum IgE and airway remodelling (mucus secreting cell numbers (MSCs), collagen deposition and epithelial thickening). Transfer of RelB^-/- CD11c⁺ DCs to RelB^-/- mice decreased pulmonary inflammation, with reduced lung chemokine and Th2-associated cytokine (IL-4/5/13/25/33, thymic stromal lymphopoietin) levels, serum IgE, numbers of type 2 innate lymphoid cells, myeloid DCs, γδ T cells and lung Vß13⁺ T cells, MSCs, airway collagen deposition and epithelial thickening.These data indicate that RelB deficiency may be a key pathway underlying AAI and that DC-encoded RelB is sufficient to restore control.]]> Wed 02 Mar 2022 14:25:08 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43636 Tue 27 Sep 2022 09:39:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39820 Tue 26 Jul 2022 11:33:21 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54347 Tue 20 Feb 2024 16:20:08 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:55703 Tue 18 Jun 2024 12:51:29 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53803 Tue 16 Jan 2024 14:59:10 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:31941 Tue 10 Apr 2018 11:22:18 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43896 Tue 05 Sep 2023 14:45:12 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40146 Tue 05 Jul 2022 15:49:42 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39910 Thu 30 Jun 2022 12:44:37 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40658 Thu 28 Jul 2022 12:42:40 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41158 Thu 28 Jul 2022 09:27:19 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48427 Thu 25 Jul 2024 15:14:51 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51168 Thu 24 Aug 2023 14:09:35 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45028 Zfp36 gene is an anti‐inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD. Methods: Here, we identify a novel protective role for TTP in CS‐induced experimental COPD using Zfp36^aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNA‐destabilising factor. TTP wild‐type (Zfp36^+/+) and Zfp36^aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. Results: After four days of CS exposure, Zfp36^aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild‐type controls. After eight weeks, Zfp36^aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema‐like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL_(S), and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS‐induced experimental COPD were ameliorated. Conclusion: Collectively, our study provides the first evidence for the therapeutic potential of inducing TTP as a treatment for COPD.]]> Thu 22 Aug 2024 13:33:30 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34512 Thu 17 Mar 2022 14:40:35 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34211 Thu 09 Dec 2021 11:02:18 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30756 Thu 03 Feb 2022 12:22:32 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33083 Thu 03 Feb 2022 12:19:51 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:14610 Sat 24 Mar 2018 08:20:47 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:11164 Sat 24 Mar 2018 08:08:30 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:16980 Sat 24 Mar 2018 07:55:27 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29786 Tnfsf10^−/−) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10^−/− mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.]]> Sat 24 Mar 2018 07:23:39 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22009 Chlamydia and Haemophilus lung infection-induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment. Results: Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor a and interleukin 17 responses that induce SSIAAD. Conclusions: Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD.]]> Sat 24 Mar 2018 07:15:55 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22085 Sat 24 Mar 2018 07:15:16 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:21997 Sat 24 Mar 2018 07:14:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48685 Mon 27 Mar 2023 14:53:41 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48673 Mon 27 Mar 2023 14:11:42 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40357 Mon 26 Aug 2024 10:30:49 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39780 Mon 25 Jul 2022 11:26:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41841 Tnfsf10^−/− BALB/c mice were administered bleomycin to induce fibrosis and some groups were treated with the FTY720 analogue AAL(s) to activate PP2A. Mouse fibroblasts were treated with recombinant TRAIL and fibrotic responses were assessed. Results: TRAIL in serum and MID1 protein levels in biopsies from IPF patients were increased compared to controls. MID1 levels were inversely associated while PP2A activity levels correlated with DLco. Tnfsf10^−/− and mice treated with the PP2A activator AAL(s) were largely protected against bleomycin-induced reductions in lung function and fibrotic changes. Addition of recombinant TRAIL to mouse fibroblasts in-vitro increased collagen production which was reversed by PP2A activation with AAL(s). Conclusion: TRAIL signalling through MID1 deactivates PP2A and promotes fibrosis with corresponding lung function decline. This may provide novel therapeutic targets for IPF.]]> Mon 15 Aug 2022 10:15:38 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46962 Il22^−/−) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22^−/− mice. Il22^−/− mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance. These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD.]]> Mon 12 Dec 2022 14:27:30 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47645 Mon 01 May 2023 15:34:21 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22044 Chlamydia, Haemophilus influenzae and Streptococcus pneumoniae in early life may promote permanent deleterious changes in immunity, lung structure, and function that predispose to, or increase the severity of chronic respiratory diseases in later life. For example, these infections increase immune responses, which drive subsequent asthma pathogenesis. Targeting the pathways involved with specific inhibitors or agonists may prevent these consequences of early-life infection. Vaccination and immunomodulatory therapies that control the infections and their sequelae may also be efficacious.]]> Mon 01 Feb 2016 13:04:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47749 Fri 27 Jan 2023 09:57:00 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33084 Fri 24 Aug 2018 15:43:54 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33077 Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. Results: Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. Conclusion: We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma.]]> Fri 24 Aug 2018 14:41:05 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33076 Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1ß responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1ß responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1ß antibody. Roles for IL-1ß-induced neutrophilic inflammation were examined using IL-1ß and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1ß responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1ß expression. Treatment with anti-IL-1ß, Ac- YVAD-cho, and MCC950 suppressed IL-1ß responses and the important steroid-resistant features of disease in mice, whereas IL-1ß administration recapitulated these features. Neutrophil depletion suppressed IL-1ß-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.]]> Fri 24 Aug 2018 14:40:56 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54960 Fri 22 Mar 2024 15:34:43 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37059 Fri 21 Aug 2020 11:53:43 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53577 Fri 08 Dec 2023 15:38:57 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33480 -/-) BALB/c mice were infected intranasally with RV1B. In separate experiments, Tnfsf10^-/- mice were sensitized and challenged via the airway route with house dust mite (HDM) to induce allergic airways disease and then challenged with RVIB or UV-RVIB. Airway hyperreactivity (AHR) was invasively assessed as total airways resistance in response to increasing methacholine challenge and inflammation was assessed in bronchoalveolar lavage fluid at multiple time points postinfection. Chemokines were quantified by ELISA of whole lung lysates and viral load was determined by quantitative RT-PCR and tissue culture infective dose (TCID₅₀). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID₅₀. HDM-challenged Tnfsf10 ^-/- mice were protected against RV-induced AHR and had suppressed cellular infiltration in the airways upon RV infection. Chemokine C-X-C-motif ligand 2 (CXCL2) production was suppressed in naïve Tnfsf10^-/- mice infected with RV1B, with less RV1B detected 24 h postinfection. This was associated with reduced apoptotic cell death and a reduction of interferon (IFN)-λ2/3 but not IFN-α or IFN-β. TRAIL stimulation increased, whereas anti-TRAIL antibodies reduced viral replication in RV1B-infected BEAS2B cells in vitro. In conclusion, TRAIL promotes RV-induced AHR, inflammation and RV1B replication, implicating this molecule and its downstream signaling pathways as a possible target for the amelioration of RV1B-induced allergic and nonallergic lung inflammation and AHR.]]> Fri 01 Apr 2022 09:25:03 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33085 -/-) and TLR4-deficient (Tlr4^-/-) mice. CS-induced airway fibrosis, characterized by increased collagen deposition around small airways, was not altered in Tlr2^-/- mice but was attenuated in Tlr4^-/- mice compared with CS-exposed WT controls. However, Tlr2^-/- mice had increased CS-induced emphysema-like alveolar enlargement, apoptosis, and impaired lung function, while these features were reduced in Tlr4^-/- mice compared with CS-exposed WT controls. Taken together, these data highlight the complex roles of TLRs in the pathogenesis of COPD and suggest that activation of TLR2 and/or inhibition of TLR4 may be novel therapeutic strategies for the treatment of COPD.]]> Fri 01 Apr 2022 09:24:33 AEDT ]]>