To investigate whether hyperpolarised xenon-129 MRI (HXeMRI) enables regional and physiological resolution of diffusing capacity limitations in chronic obstructive pulmonary disease (COPD), we evaluated 34 COPD subjects and 11 healthy volunteers. We report significant correlations between airflow abnormality quantified by HXeMRI and per cent predicted forced expiratory volume in 1 s; HXeMRI gas transfer capacity to red blood cells and carbon monoxide diffusion capacity (%DLCO); and HXeMRI gas transfer capacity to interstitium and per cent emphysema quantified by multidetector chest CT. We further demonstrate the capability of HXeMRI to distinguish varying pathology underlying COPD in subjects with low %DLCO and minimal emphysema.

Purpose: Heterogeneous nature of Chronic Obstructive Pulmonary Disease (COPD) must be comprehensively addressed. It is unclear if integrative multidisciplinary disease management (IMDM) can optimize clinical outcomes of patients with COPD. Methods: A single-center, retrospective cohort observational study with a historical intervention was conducted in a clinic specialized for COPD care. Patients with a confirmed diagnosis of COPD were administered IMDM with measurement of BODE score on initial and follow-up visits. Primary outcomes were dynamic changes in BODE quartiles after receiving IMDM. Results: Of 124 patients, 21% were misdiagnosed with COPD. Patients with a confirmed diagnosis of COPD were 50% female, median age 64 years (IQR 57-70), 43% actively smoking and initial visit median BODE quartile 2 (IQR 1-3). Three subgroups were identified based on the changes in BODE quartiles: worsened (21%), unchanged (55%) and improved (24%). At baseline, mMRC (median [IQR]) was higher in improved subgroup vs worsened and unchanged subgroup (3 [3, 4] vs 2 [1, 2] vs 2 [1, 3], p value 0.002) respectively. Drop in all components of BODE score was noted in worsened group, but significant improvement in mMRC with preservation of spirometry values was noted in the improved group. The incidence of smoking cigarettes changed from 39% to 26% during follow-up. Conclusion: Our study demonstrates that IMDM can be potentially effective in a subgroup of COPD patients. In others precipitous drop in lung function, activity tolerance, and subjective symptoms seems inevitable with worsening BODE quartiles.

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Emphysema is a unique type of chronic obstructive pulmonary disease, and sex may influence susceptibility. After cigarette smoke exposure, murine males and ovariectomized females developed more severe emphysema. Herein, we present divergent bulk and single-cell transcriptomic profiles between male and female murine lungs. Weighted Gene Co-Expression Network Analysis of the bulk lung RNA sequencing identified a Green gene module that correlated with male sex and ovariectomy. The Green gene module was enriched in common monocyte progenitors, classical monocytes, type 1 dendritic cells, and macrophages from 83,698 murine cells exposed to air or cigarette smoke for five months. Sexual dimorphism altered the compositions and transcriptome of the clusters enriched with the Green gene module. This comprehensive transcriptomic analysis advances our understanding of dynamic cellular responses controlled by sexual dimorphism during the development of emphysematous pulmonary tissue remodeling and reveals potential targets for mechanistic studies in the future.

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Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation due to damage in either the pulmonary parenchyma or airways. It has been suggested that males are more susceptible to emphysema, and females to chronic bronchitis. However, the mechanism underlying the effect of sex on the extent of emphysematous destruction has not been clearly elucidated. The goals of this study are to identify sex-specific differences in murine pulmonary emphysema induced by exposure to cigarette smoke, and to determine pathways that may explain this variation. Methods: Male and female C57BL/6 mice were exposed to 0, 3, and 5 months of cigarette smoke, or sham air at 0 and 5 months (n=5 per group). Morphometry was assessed in murine lungs inflated at 30 cmH 2 O. Total lung RNA was sequenced by Illumina PE150, and differentially expressed genes and pathways were analyzed. Results: A significant dose-dependent increase in chord length, correlating with worsening emphysema, was observed in male mice independent of age-related changes, but not in females. RNAseq revealed 1874 differentially expressed genes in males (908 upregulated and 966 downregulated) after 5 months of smoking, and 1557 differentially expressed genes in females (966 upregulated and 591 downregulated), with adjusted p<0.05. Among the 80 differentially expressed genes between female and male smoked mice, 51 were relatively upregulated in males and 29 in females. Besides the upregulation of inactive X-specific transcripts in females, and DEAD-box polypeptide and translation initiation factor in males, the most notably different genes expressed between female and male smoked mice were those of histone demethylases on chromosomes X and Y respectively, suggesting that histone modification is key in their response to cigarette smoke, possibly in a sex-specific manner. Enrichment analysis using Gene Ontology (GO) and Reactome databases demonstrated that extracellular matrix pathways are significantly downregulated with smoke exposure, but not influenced by sex. Between the sexes, pathways in the GO database related to VEGF, integrin binding, and insulin-like growth factor were relatively upregulated in males compared to females, whereas those of interleukin-8, interferon-gamma, macrophage activation, and NF-kappaB were downregulated. Using Reactome (see figure), males had a significant downregulation of Tolllike receptor cascade and translation pathways. Conclusion:This study demonstrates that changes in the extracellular matrix after cigarette smoking are not explained by sex, whereas pathways related to immune response and regulation of protein translation may contribute to the relative resistance against emphysema observed in female C57BL/6 mice.

Emphysema is characterized by the permanent enlargement of distal airspaces. Current therapies focus on symptom relief as little can halt disease progression. Given its role in cell aging/damage, the mTOR pathway has been studied with respect to emphysema. While inhibition of this pathway with rapamycin has been shown to delay progression of cigarette-smoke (CS) induced emphysema, effects of gender have not been examined. We aim to characterize the effects of rapamycin on the progression of CS induced lung injury in male and female mice.