A retrospective study of crossover ambulatory oxygen walk testing in patients with fibrotic lung disease.

BACKGROUND: Fibrotic interstitial lung disease (ILD) comprises a group of lung conditions that are often progressive, debilitating, and life-shortening. Ambulatory oxygen therapy (AOT) is regularly prescribed to manage symptoms in patients with fibrotic ILD. In our institution, the decision to prescribe portable oxygen is made on the basis of oxygen improving exercise capacity, measured with the single-blinded, crossover ambulatory oxygen walk test (AOWT). This study aimed to investigate the characteristics and survival rates of patients with fibrotic ILD who have either positive or negative results on the AOWT. METHODS: This retrospective cohort study compared the data from 99 patients with fibrotic ILD who underwent the AOWT. These patients were classified into two groups based on whether they showed improvement in the AOWT with supplemental oxygen (positive group) or no improvement (negative group). Patient demographics for both groups were compared to determine any significant differences. A multivariate Cox proportional hazards model was used to analyze the survival rates of the two groups. RESULTS: Out of the 99 patients, 71 were in the positive group. We compared the measured characteristics between the positive and negative groups and found no significant difference, wherein the adjusted hazard ratio was 1.33 (95% confidence interval 0.69-2.60, P = 0.40). CONCLUSIONS: The AOWT can be used to rationalize AOT, but there was no significant difference in baseline characteristics or survival rates between patients whose performance was improved or not in the AOWT.

Sources of non-methane hydrocarbons in surface air in Delhi, India.

Rapid economic growth and development have exacerbated air quality problems across India, driven by many poorly understood pollution sources and understanding their relative importance remains critical to characterising the key drivers of air pollution. A comprehensive suite of measurements of 90 non-methane hydrocarbons (NMHCs) (C2-C14), including 12 speciated monoterpenes and higher molecular weight monoaromatics, were made at an urban site in Old Delhi during the pre-monsoon (28-May to 05-Jun 2018) and post-monsoon (11 to 27-Oct 2018) seasons using dual-channel gas chromatography (DC-GC-FID) and two-dimensional gas chromatography (GC×GC-FID). Significantly higher mixing ratios of NMHCs were measured during the post-monsoon campaign, with a mean night-time enhancement of around 6. Like with NOx and CO, strong diurnal profiles were observed for all NMHCs, except isoprene, with very high NMHC mixing ratios between 35-1485 ppbv. The sum of mixing ratios of benzene, toluene, ethylbenzene and xylenes (BTEX) routinely exceeded 100 ppbv at night during the post-monsoon period, with a maximum measured mixing ratio of monoaromatic species of 370 ppbv. The mixing ratio of highly reactive monoterpenes peaked at around 6 ppbv in the post-monsoon campaign and correlated strongly with anthropogenic NMHCs, suggesting a strong non-biogenic source in Delhi. A detailed source apportionment study was conducted which included regression analysis to CO, acetylene and other NMHCs, hierarchical cluster analysis, EPA UNMIX 6.0, principal component analysis/absolute principal component scores (PCA/APCS) and comparison with NMHC ratios (benzene/toluene and i-/n-pentane) in ambient samples to liquid and solid fuels. These analyses suggested the primary source of anthropogenic NMHCs in Delhi was from traffic emissions (petrol and diesel), with average mixing ratio contributions from Unmix and PCA/APCS models of 38% from petrol, 14% from diesel and 32% from liquified petroleum gas (LPG) with a smaller contribution (16%) from solid fuel combustion. Detailed consideration of the underlying meteorology during the campaigns showed that the extreme night-time mixing ratios of NMHCs during the post-monsoon campaign were the result of emissions into a very shallow and stagnant boundary layer. The results of this study suggest that despite widespread open burning in India, traffic-related petrol and diesel emissions remain the key drivers of gas-phase urban air pollution in Delhi.

An increasing role for solvent emissions and implications for future measurements of volatile organic compounds.

Volatile organic compounds (VOCs) are a broad class of air pollutants which act as precursors to tropospheric ozone and secondary organic aerosols. Total UK emissions of anthropogenic VOCs peaked in 1990 at 2,840 kt yr-1 and then declined to approximately 810 kt yr-1 in 2017 with large reductions in road transport and fugitive fuel emissions. The atmospheric concentrations of many non-methane hydrocarbons (NMHC) in the UK have been observed to fall over this period in broadly similar proportions. The relative contribution to emissions from solvents and industrial processes is estimated to have increased from approximately 35% in 1990 to approximately 63% in 2017. In 1992, UK national monitoring quantified 19 of the 20 most abundant individual anthropogenic VOCs emitted (all were NMHCs), but by 2017 monitoring captured only 13 of the top 20 emitted VOCs. Ethanol is now estimated to be the most important VOC emitted by mass (in 2017 approx. 136 kt yr-1 and approx. 16.8% of total emissions) followed by n-butane (52.4 kt yr-1) and methanol (33.2 kt yr-1). Alcohols have grown in significance representing approximately 10% of emissions in 1990 rising to approximately 30% in 2017. The increased role of solvent emissions should now be reflected in European monitoring strategies to verify total VOC emission reduction obligations in the National Emissions Ceiling Directive. Adding ethanol, methanol, formaldehyde, acetone, 2-butanone and 2-propanol to the existing NMHC measurements would provide full coverage of the 20 most significant VOCs emitted on an annual mass basis. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Predicting outcomes in rheumatoid arthritis related interstitial lung disease.

The aim of this study was to compare radiology-based prediction models in rheumatoid arthritis-related interstitial lung disease (RAILD) to identify patients with a progressive fibrosis phenotype.RAILD patients had computed tomography (CT) scans scored visually and using CALIPER and forced vital capacity (FVC) measurements. Outcomes were evaluated using three techniques, as follows. 1) Scleroderma system evaluating visual interstitial lung disease extent and FVC values; 2) Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and 3) CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients.On univariable Cox analysis, all three staging systems strongly predicted outcome (scleroderma system hazard ratio (HR) 3.78, p=9×10-5; Fleischner system HR 1.98, p=2×10-3; and 4.4% VRS threshold HR 3.10, p=4×10-4). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n=36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multivariable analysis, with adjustment for patient age, sex and smoking status, when analysed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcome (model C-statistic 0.77).The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent.

4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C.

Mutations in the SFTPC gene, encoding surfactant protein-C (SP-C), are associated with interstitial lung disease (ILD). Knowledge of the intracellular fate of mutant SP-C is essential in the design of therapies to correct trafficking/processing of the proprotein, and to prevent the formation of cytotoxic aggregates. We assessed the potential of a chemical chaperone to correct the trafficking and processing of three disease-associated mutant SP-C proteins. HEK293 cells were stably transfected with wild-type (SP-C(WT)) or mutant (SP-C(L188Q), SP-C(Δexon4), or SP-C(I73T)) SP-C, and cell lines with a similar expression of SP-C mRNA were identified. The effects of the chemical chaperone 4-phenylbutyric acid (PBA) and lysosomotropic drugs on intracellular trafficking to the endolysosomal pathway and the subsequent conversion of SP-C proprotein to mature peptide were assessed. Despite comparable SP-C mRNA expression, proprotein concentrations varied greatly: SP-C(I73T) was more abundant than SP-C(WT) and was localized to the cell surface, whereas SP-C(Δexon4) was barely detectable. In contrast, SP-C(L188Q) and SP-C(WT) proprotein concentrations were comparable, and a small amount of SP-C(L188Q) was localized to the endolysosomal pathway. PBA treatment restored the trafficking and processing of SP-C(L188Q) to SP-C(WT) concentrations, but did not correct the mistrafficking of SP-C(I73T) or rescue SP-C(Δexon4). PBA treatment also promoted the aggregation of SP-C proproteins, including SP-C(L188Q). This study provides proof of the principle that a chemical chaperone can correct the mistrafficking and processing of a disease-associated mutant SP-C proprotein.

Expression of the developmental Sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes.

During pulmonary development, Sonic hedgehog (Shh) and transforming growth factor beta1 (TGF-beta1) signalling both contribute to branching morphogenesis. In interstitial lung disease, the complex alveolar structure of the lung is disrupted and remodelled, which leads to fibrosis, loss of respiratory surface, morbidity, and mortality. It is well documented that TGF-beta1 is involved in fibrosis. However, little is known about Shh signalling in damaged epithelia. This study examined whether or not components of the Shh signalling pathway, as well as TGF-beta1, are expressed in human fibrotic lung disease (cryptogenic fibrosing alveolitis and bronchiectasis) and in murine experimental models of fibrotic and non-fibrotic chronic pulmonary inflammation. Using immunohistochemistry, it was observed that Shh, like TGF-beta1, is up-regulated in epithelial cells at sites of fibrotic disease but not non-fibrotic inflammation. The Shh receptor patched was detected in infiltrating mononuclear cells and alveolar macrophages, as well as normal resting peripheral blood T lymphocytes. Neither Shh nor patched is expressed by hyperproliferative goblet cells in inflammatory epithelium. This study demonstrates that patched is present in human peripheral CD4 and CD8 lymphocytes at both protein and mRNA levels. Taken together, these results suggest that components of the highly conserved Shh signalling pathway may play a role in the remodelling of damaged pulmonary epithelium and that damaged epithelium and cells of the immune system may communicate via this pathway.

Sonic hedgehog signaling modulates activation of and cytokine production by human peripheral CD4+ T cells.

Sonic hedgehog (Shh) is important in the growth and differentiation of a variety of cell types, including the development of T cells in the thymus. This prompted us to investigate whether Shh signaling is a functional component of the physiological response of human mature CD4(+) T cells following Ag recognition. In this study, we demonstrate that Shh and its receptor Patched (Ptc) are expressed on resting and activated human peripheral CD4(+) T cells. In approximately one-half of the randomly selected, anonymous blood donors tested, exposure of anti-CD3/28 Ab-activated CD4(+) T cells to the biologically active N-terminal Shh peptide increased the transcription of ptc, thereby demonstrating that Shh signaling had occurred. Furthermore, the addition of exogenous Shh amplified the production of IL-2, IFN-gamma, and IL-10 by activated CD4(+) T cells. The synthesis of IL-2 and IFN-gamma, but not IL-10, by CD4(+) T cells was down-regulated by the addition of neutralizing anti-Shh Ab. Cell surface expression of CD25 and CD69 on activated T cells was up-regulated by exogenous Shh, whereas in the presence of the neutralizing anti-Shh Ab expression it was reduced. Collectively, our findings demonstrate that Shh-mediated signaling is a physiological component of T cell responses, which acts to modulate CD4(+) T cell effector function.

Sonic hedgehog promotes cell cycle progression in activated peripheral CD4(+) T lymphocytes.

Sonic hedgehog (Shh) signaling is important in the growth and differentiation of many cell types and recently has been reported to play a role in T cell development in the thymus. This prompted us to investigate whether or not Shh contributes to the clonal expansion of peripheral CD4(+) T cells. In this study, we demonstrate that Shh and other components of the signaling pathway patched, smoothened, and Gli1 (glioma-associated oncogene) are expressed in peripheral CD4(+) T cells. The addition of the biologically active amino-terminal Shh peptide had no effect on resting CD4(+) T cells, but significantly enhanced proliferation of anti-CD3/28 Ab-activated CD4(+) T cells. This was not due to antiapoptotic effects, but by promoting entry of T cells into the S-G(2) proliferative phase of the cell cycle. Neutralizing anti-Shh Ab reduced T cell proliferation by inhibiting cell transition into the S-G(2) phase, suggesting that endogenously produced Shh plays a physiological role in the clonal expansion of T cells. Furthermore, we have observed a significant up-regulation of Shh and Gli1 (glioma-associated oncogene) mRNA in activated CD4(+) T cells with or without addition of exogenous Shh, which corresponds with maximal CD4(+) T cell proliferation, whereas bcl-2 was only up-regulated in activated cells in the presence of Shh. Our findings suggest that endogenously produced Shh may play a role in sustaining normal CD4(+) T cell proliferation and exogenously added Shh enhances this response.