88 research outputs found
Structural and functional correlations in a large animal model of bleomycin-induced pulmonary fibrosis
No full textBACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Pre-clinical animal models are currently largely limited to small animals which have a number of shortcomings. We have previously shown that fibrosis is induced in isolated sheep lung segments 14 days after bleomycin treatment. This study aimed to determine whether bleomycin-induced fibrosis and associated functional changes persisted over a seven-week period. METHODS: Two separate lung segments in nine sheep received two challenges two weeks apart of either, 3U bleomycin (BLM), or saline (control). Lung function in these segments was assessed by a wedged-bronchoscope procedure after bleomycin treatment. Lung tissue, and an ex vivo CT analysis were used to assess for the persistence of inflammation, fibrosis and collagen content in this model. RESULTS: Fibrotic changes persisted up to seven weeks in bleomycin-treated isolated lung segments (Pathology scores: bleomycin12.27 +/- 0.07 vs. saline 4.90 +/- 1.18, n = 9, p = 0.0003). Localization of bleomycin-induced injury and increased tissue density was confirmed by CT analysis (mean densitometric CT value: bleomycin -698 +/- 2.95 Hounsfield units vs. saline -898 +/- 2.5 Hounsfield units, p = 0.02). Masson s trichrome staining revealed increased connective tissue in bleomycin segments, compared to controls ( blue staining/total field area: 8.5 +/- 0.8 vs. 2.1 +/- 0.2 , n = 9, p <0.0001). bleomycin-treated segments were significantly less compliant from baseline at 7 weeks post treatment compared to control-treated segments (2.05 +/- 0.88 vs. 4.97 +/- 0.79 mL/cmH20, n = 9, p = 0.002). There was also a direct negative correlation between pathology scores and segmental compliance. CONCLUSIONS: We show that there is a correlation between fibrosis and correspondingly poor lung function which persist for up to seven weeks after bleomycin treatment in this large animal model of pulmonary fibrosis
Supplemental material for Changes in duodenal CD163-positive cells in dogs with chronic enteropathy after successful treatment
No full textSupplemental material for Changes in duodenal CD163-positive cells in dogs with chronic enteropathy after successful treatment by Julien RS Dandrieux, Lina Maria Martinez Lopez, Andrew Stent, Albert Jergens, Karin Allenspach, Cameron J Nowell, Simon M Firestone, Wayne Kimpton and Caroline S Mansfield in Innate Immunity</p
Flow Cytometric Cell Sorter
No full textA/Pr Wayne G Kimpton$AUD 70,000.00NHMRC Infrastructure GrantsEquipment Gran
Role of the thymus in tissue-specific homing to lymph n odes spleen and gut
No full textA/Pr Wayne G Kimpton$AUD 240,635.78NHMRC Project GrantsStandard Project Gran
Role of the thymus in tissue-specific homing to lymph n odes, spleen and gut
No full textA/Pr Wayne G Kimpton$AUD 72,840.79NHMRC Project GrantsStandard Project Gran
An analysis of cell populations recirculating through n ormal and inflamed joints in vivo
No full textA/Pr Wayne G Kimpton$AUD 34,276.06NHMRC Project GrantsStandard Project Gran
A novel segmental challenge model for bleomycin-induced pulmonary fibrosis in sheep
No full textBackground: Idiopathic Pulmonary fibrosis (IPF) is a fatal respiratory disease, characterized by a progressive fibrosis and worsening lung function. While the outcomes of recent clinical trials have resulted in therapies to slow the progression of the disease, there is still a need to develop alternative therapies, which are able to prevent fibrosis. Aim: This study uses a segmental lung infusion of bleomycin (BLM) to investigate pulmonary fibrosis in a physiologically relevant large animal species. Methods: Two separate lung segments in eight sheep received two fortnightly challenges of either 3U or 30U BLM per segment, and a third segment received saline (control). Lung function was assessed using a wedged-bronchoscope procedure. Bronchoalveolar lavage fluid and lung tissue were assessed for inflammation, fibrosis and collagen content two weeks after the final dose of BLM. Results: Instillation of both BLM doses resulted in prominent fibrosis in the treated lobes. More diffuse fibrosis and loss of alveolar airspace was observed in high-dose BLM-treated segments, while multifocal fibrosis was seen in low-dose BLM-treated segments. Extensive and disorganised collagen deposition occurred in the BLM-treated lobes, compared to controls. Significant loss of lung compliance was also observed in the BLM-treated lobes, which did not occur in controls. Conclusions: Fibrosis comparable to IPF was induced into isolated lung segments, without compromising the respiratory functioning of the animal. This model may have potential for investigating novel therapies for IPF by allowing direct comparison of multiple treatments with internal controls, and sampling and drug delivery that are clinically relevant
Inhibition of the KCa3.1 channel alleviates established pulmonary fibrosis in a large animal model
No full textIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease of increasing prevalence marked by poor prognosis and limited treatment options. Ca21-activated KCa3.1 potassium channels have been shown to play a key role in the aberrant activation and responses to injury in both epithelial cells and fibroblasts, both considered key drivers in the fibrotic process of IPF. Pharmacological inhibition of IPF-derived fibroblasts is able to somewhat prevent TGF-b- and basic fibroblast growth factor-dependent profibrotic responses. In the current study, we investigated whether blockade of theKCa3.1 ion channel in vivo with a selective inhibitor, Senicapoc, was able to attenuate both histological and physiological outcomes of early fibrosis in our large animal (sheep) model for pulmonary fibrosis.We also determined whether treatment was targeting the profibrotic activity of sheep lung fibroblasts. Senicapoc was administered in established fibrosis, at 2 weeks after bleomycin instillation, and drug efficacy was assessed 4 weeks after treatment. Treatment with Senicapoc improved pre-established bleomycin-induced changes compared with vehicle control, leading to improved lung compliance, reduced extracellular matrix and collagen deposition, and a reduction in both a-smooth muscle actin expression and proliferating cells, both in vivo and in vitro. These studies show that inhibiting the KCa3.1 ion channel is able to attenuate the early fibrogenic phase of bleomycin-dependent fibrosis and inhibits profibrotic behavior of primary sheep lung fibroblasts. This supports the previous research conducted in human IPF-derived fibroblasts and suggests that inhibiting KCa3.1 signaling may provide a novel therapeutic approach for IPF
The temporality of on-street parking – exploring the role of land-use mix and change on parking dynamics
No full textFunding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Australian Research Council (LP160100031). Publisher Copyright: © The Author(s) 2022.Parking is often overlooked by urban researchers even though parking consumes large proportions of a city’s physical footprint and imposes a significant impediment to more sustainable travel. Underpinning this lack of attention is suitable data and methods capable of capturing the complex dynamics of parking. Here we redress this gap by drawing on an emergent source of parking data and deploying empirical techniques to unpack this complexity. Data from 3542 on-street parking sensors observed over a 9-year period are used to delineate the first typology of parking routines before using a fixed-effects logistic regression model to explain how nearby land-use types and land-use mix shapes tempo and timing of parking utilisation. The benefit of our approach lies in its capacity to discriminate broad types of temporal rhythms associated with parking dynamics at particular places, how these change over time and how these rhythms are associated with different types and mixes of nearby land use. This knowledge is important to inform policies seeking to optimise the use of on-street parking and invoke more sustainable patterns of mobility.Peer reviewe
Setting the agenda for parking research in other cities
No full textThe chapter reflects on the 12 case studies discussed in the book and considers their implications for future research. At the end of the chapter, a new agenda for parking research in large cities is set out.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Spatial Planning and Strateg
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