Predicting spatial variations in annual average outdoor ultrafine particle concentrations in Montreal and Toronto, Canada: Integrating land use regression and deep learning models.

BACKGROUND: Concentrations of outdoor ultrafine particles (UFP; <0.1 µm) and black carbon (BC) can vary greatly within cities and long-term exposures to these pollutants have been associated with a variety of adverse health outcomes. OBJECTIVE: This study integrated multiple approaches to develop new models to estimate within-city spatial variations in annual median (i.e. average) outdoor UFP and BC concentrations as well as mean UFP size in Canada's two largest cities, Montreal and Toronto. METHODS: We conducted year-long mobile monitoring campaigns in each city that included evenings and weekends. We developed generalized additive models trained on land use parameters and deep Convolutional Neural Network (CNN) models trained on satellite-view images. Using predictions from these models, we developed final combined models. RESULTS: In Toronto, the median observed UFP concentration, UFP size, and BC concentration values were 16,172pt/cm3, 33.7 nm, and 1225 ng/m3, respectively. In Montreal, the median observed UFP concentration, UFP size, and BC concentration values were 14,702pt/cm3, 29.7 nm, and 1060 ng/m3, respectively. For all pollutants in both cities, the proportion of spatial variation explained (i.e., R2) was slightly greater (1-2 percentage points) for the combined models than the generalized additive models and a greater (approximately 10 percentage points) than the deep CNN models. The Toronto combined model R2 values in the test set were 0.73, 0.55, and 0.61 for UFP concentrations, UFP size, and BC concentration, respectively. The Montreal combined model R2 values were 0.60, 0.49, and 0.60 for UFP concentration, UFP size, and BC concentration models respectively. For each pollutant, predictions from the combined, deep CNN, and generalized additive models were highly correlated with each other and differences between models were explored in sensitivity analyses. CONCLUSION: Predictions from these models are available to support future epidemiological research examining long-term health impacts of outdoor UFPs and BC.

Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms.

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.

HB-EGF Synthesized by CD4 T Cells Modulates Allergic Airway Eosinophilia by Regulating IL-5 Synthesis.

CD4 T cells express the epidermal growth factor (EGF) receptor ligand, heparin-binding EGF (HB-EGF), with no defined immuno-pathophysiological function. Therefore, we wished to elucidate the function of HB-EGF synthesized by CD4 T cells in the context of allergic pulmonary inflammation and the asthma surrogate, airway hyperresponsiveness, in a murine acute model of asthma. In this study, we show how knocking out HB-EGF expression in CD4 T cells in vivo attenuates IL-5 synthesis in the lung that is accompanied by diminished eosinophilic inflammation and airway hyperresponsiveness. HB-EGF coimmunoprecipitates with the transcriptional repressor B cell lymphoma 6 (Bcl-6) in CD4 T cells. Knocking out HB-EGF in CD4 T cells resulted in increased Bcl-6 binding to the IL-5 gene and decreased IL-5 mRNA expression. Thus, these findings suggest an immunoregulatory function for intrinsic HB-EGF expressed by CD4 T cells in TH2 inflammation and airway dysfunction by modulating IL-5 expression via binding to and inhibiting the repressive function of Bcl-6.

Human airway branch variation and chronic obstructive pulmonary disease.

Susceptibility to chronic obstructive pulmonary disease (COPD) beyond cigarette smoking is incompletely understood, although several genetic variants associated with COPD are known to regulate airway branch development. We demonstrate that in vivo central airway branch variants are present in 26.5% of the general population, are unchanged over 10 y, and exhibit strong familial aggregation. The most common airway branch variant is associated with COPD in two cohorts (n = 5,054), with greater central airway bifurcation density, and with emphysema throughout the lung. The second most common airway branch variant is associated with COPD among smokers, with narrower airway lumens in all lobes, and with genetic polymorphisms within the FGF10 gene. We conclude that central airway branch variation, readily detected by computed tomography, is a biomarker of widely altered lung structure with a genetic basis and represents a COPD susceptibility factor.