Defective lung macrophage function in lung cancer +/- chronic obstructive pulmonary disease (COPD/emphysema)-mediated by cancer cell production of PGE2?

In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective ‘efferocytosis’), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells. We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis. Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown. Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2.Francis C. Dehle, Violet R. Mukaro, Craig Jurisevic, David Moffat, Jessica Ahern, Greg Hodge, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodg

Lectins offer new perspectives in the development of macrophage-targeted therapies for COPD/emphysema

We have previously shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells (‘efferocytosis’) in chronic obstructive pulmonary disease/emphysema (COPD) could be therapeutically improved using the C-type lectin, mannose binding lectin (MBL), although the exact mechanisms underlying this effect are unknown. An S-type lectin, galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98. We hypothesized that defective expression of galectin/CD98 would be associated with defective efferocytosis in COPD and that mechanisms would include effects on cytoskeletal remodeling and macrophage phenotype and glutathione (GSH) availability. Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of galectin-3 on efferocytosis, CD98, GSH, actin polymerisation, rac activation, and the involvement of PI3K (using β-actin probing and wortmannin inhibition) in vitro using human AM and/or MH-S macrophage cell line. Significant decreases in BAL galectin-3 and AM CD98 were observed in BAL from both current- and ex-smoker COPD subjects vs controls. Galectin 3 increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with β-actin probing and the role of PI3K was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98. We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies.Violet R. Mukaro, Johan Bylund, Greg Hodge, Mark Holmes, Hubertus Jersmann, Paul N. Reynolds, Sandra Hodg

Bacterial lipopolysaccharide and tumour necrosis factor- alpha synergism in inflammation / Hubertus Paul Anton Jersmann.

Bibliography: leaves 152-194.xxi, 194 leaves : ill. (some col.) ; 30 cm.This thesis has contributed to the knowledge of how the bacteriokine-cytokine network operates by demonstrating how two major proinflammatory mediators interact in modulating the inflammatory response. Furthermore the discovery of CD14 expression on endothelial cells not only provides greater insight in the pathogenesis of bacterial infection, sepsis and perhaps atherosclerosis, it is also likely to influence the future development of new treatment strategies for those conditions.Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 200

HTLV-1c associated bronchiolitis in an Aboriginal man from central Australia

We describe the first case of HTLV associated bronchiolitis to be associated with HTLV-1c subtype infection. An Aboriginal man with HTLV-1 infection was repeatedly admitted to Alice Springs Hospital, central Australia, with hypercapnic respiratory failure from the age of 28 years. High resolution CT chest findings were consistent with bronchiolitis and large numbers of lymphocytes were found in bronchoalveolar lavage fluid (BALF). After extensive investigations failed to find a cause, he was tested for HTLV-1 and found to have a high HTLV-1c proviral load (6.8 %) in peripheral blood leukocytes and in BALF (4.7 %). The administration of systemic corticosteroids resulted in a rapid clinical response; however, he did not continue treatment after discharge and died due to respiratory failure in the community. Keywords: HTLV-1, Bronchiolitis, Indigenous healt

Sleep Disordered Breathing and Polysomnography in Australia: Trends in Provision from 2005 to 2012 and the Impact of Home-Based Diagnosis

Study Objectives: To describe the growth of publicly funded polysomnography (PSG) in Australia since 2004 and to compare this with earlier growth. Methods: Longitudinal census-level data stratified by jurisdiction were retrieved from the Medicare Australia online database. Results: There has been a near doubling in provision of PSG since the introduction of publicly funded in-home PSG under the Australian national Medicare program available to all Australian citizens in 2008. Overall annual PSG rates have risen from 339 in 2005 to 608 in 2012 per 100,000. This growth has exceeded that of comparable diagnostic procedures and all Medicare services overall. Queensland remains the leading jurisdiction per 100,000 Medicare enrollees for accessing Medicare-funded PSG. Conclusion: The continued growth in publicly funded PSG provision in Australia is unlikely to abate. The disparity in Australia between the estimated prevalence of sleep disorders, particularly obstructive sleep apnea, and the number of people having PSGs would suggest there remain a large number of undiagnosed cases. Support for the development of appropriate diagnostic and screening algorithms will be key in ensuring sustainable, effective, efficient, and accessible PSG services