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Background: Extrapulmonary manifestations including cognitive impairment, reduced muscle and cardiovascular function is common in COPD. While high-intensity exercise offers extrapulmonary benefits, its implementation in COPD is challenging. This randomised cross-over trial examined the feasibility and physiological responses of a novel supramaximal high-intensity interval-training (SupraHIIT) protocol compared to moderate-intensity continuous training (MICT) in people with COPD and matched healthy controls (HCs).

Methods: Sixteen people with COPD and 16 HCs performed SupraHIIT and MICT. SupraHIIT consisted of 10x6 sec intervals at ≈150% and ≈200% of maximum aerobic power (MAP), while MICT was performed for 20 min at 60% of MAP. Outcomes were exercise intensity, change in exerkines, feasibility, and cardiorespiratory demand of the modalities.

Results: SupraHIIT was feasible and enabled up to a 3.5-fold increase in external exercise intensity compared to MICT (184±66 and 245±88 watt versus 71±22 watt in COPD, p<0.001). All participants could complete SupraHIIT which was the preferred modality in both groups (p<0.01) while 5/16 participants with COPD interrupted MICT due to intolerable dyspnea or exhaustion (p=0.005). Both modalities increased plasma brain-derived neurotrophic factor (pBDNF) by an average of 59% (range 30%-87%, p<0.05). When normalised for duration at target power, SupraHIIT produced a 5–10-fold greater increase than MICT. Both modalities lead to a variable response in other exerkines including clusterin, lactate, hepatocyte growth factor and interleukin-6.

Conclusion: In COPD, short duration SupraHIIT is more feasible and enables markedly higher external exercise intensities than MICT. By elevating pBDNF and other potentially beneficial exerkines, it shows potential for extrapulmonary benefits.

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs, mostly affecting young and middle-aged women. Significant questions remain as to its pathogenesis, especially the triggers for the associated interstitial lung disease (SSc-ILD). We examined the extent to which SSc and SSc-ILD were related to oxidative stress and altered metal homeostasis at the air-lung interface.

Methods: In this case-control study, we recruited 20 SSc patients, of which 11 had SSc-ILD. Eighteen healthy individuals were recruited as age-matched healthy controls, for a total of 38 study participants. Low molecular weight antioxidants (ascorbate, urate and glutathione), metal transport and chelation proteins (transferrin and ferritin) and metals (Fe and Cu) concentrations, including a measure of the catalytically active metal pool, were determined in respiratory tract lining fluid (RTLF) collected by bronchoalveolar lavage from the SSc group and compared with healthy controls.

Results: In the SSc group, 14 individuals were of female sex (70%) and the median age was 57 years (range 35–75). We observed evidence of oxidative stress in the RTLFs of SSc patients, characterised by increased concentrations of glutathione disulphide (GSSG, P<0.01), dehydroascorbate (DHA, P<0.05) and urate (P<0.01). This was associated with elevated RTLF Fe (P=0.07) and Cu (P<0.001), and evidence of a catalytic metal pool, demonstrated by an enhanced rate of ascorbate oxidation in the recovered lavage fluid (p<0.01). Cu concentrations were significantly associated with the ascorbate depletion rate (r=0.76, P<0.001), and GSSG (r=0.38, P<0.05) and protein carbonyl (r=0.44, P<0.01) concentrations. Whilst these markers were all increased in SSc patients, we found no evidence for an association with SSc-ILD.

Conclusions: These data confirm the presence of oxidative stress in the airways of SSc patients and, for the first time, suggest that an underlying defect in metal homeostasis at the air-lung interface may play a role in disease progression.

Objectives: The adipocyte-derived hormone leptin has been associated with the pathogenesis of cardiovascular disease. The mechanisms underlying this association are unclear but may relate to effects on the vascular endothelium. Our aim was to explore the effects of leptin on endothelial vasomotor and fibrinolytic function in healthy volunteers and patients with coronary artery disease.

Design: The vascular effects of leptin were assessed infusing recombinant human leptin in healthy volunteers during measuring vasomotor response by venous occlusion plethysmography. Additionally, circulating levels of leptin were analysed in relation to endothelial dysfunction in patients with established coronary artery disease.

Results: In healthy male volunteers, intra-arterial infusion of recombinant human leptin (80, 800 and 8,000 ng/min; n = 10) did not affect basal forearm blood flow, plasma tissue plasminogen activator (tPA) or plasminogen activator inhibitor type 1 concentrations (all p > 0.05). However, during concomitant co-infusion with leptin (800 ng/min; n = 10), drug-induced vasodilatation was reduced (p = 0.001), and tPA activity increased (p = 0.002). In patients with coronary artery disease, those with the high plasma leptin levels had reduced drug-induced vasodilatation (p < 0.001), and increased net release of tPA antigen and activity (p < 0.001 and p = 0.03, respectively) compared to those with low levels. The study has been registered retrospectively at Clinical Trials with number NCT04374500.

Conclusion: Intrabrachial leptin infusion did not affect the basal vascular tone, whereas acute and chronic hyperleptinemia was associated with blunted vasoreactivity in healthy volunteers, and in patients with coronary artery disease.

Background: Exposure to standard petrodiesel exhaust is linked to adverse health effects. Moreover, there is a mounting request to replace fossil-based fuels with renewable and sustainable alternatives and, therefore, rapeseed methyl ester (RME) and other biofuels have been introduced. However, recent toxicological research has indicated that biodiesel exhaust may also induce adverse health-related events.

Aim: To determine whether exposure to 100% RME biodiesel (BD100) exhaust would cause an acute airway neutrophilic recruitment in humans.

Methods: Fourteen healthy subjects underwent exposure to diluted BD100 exhaust and filtered air for 1-h, in a blinded, random fashion. Bronchoscopy with endobronchial mucosal biopsies, bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed six hours after exposure. Differential cell counts and inflammatory markers were determined in the supernatant and biopsies were stained immunohistochemically.

Results: Compared with filtered air, BD100 exhaust exposure increased bronchial mucosal endothelial P-selectin adhesion molecule expression, as well as neutrophil, mast cell and CD68 + macrophage numbers. An increased influx of neutrophils and machrophages was also seen in BW.

Conclusion: Exposure to biodiesel exhaust was associated with an acute airway inflammation that appeared similar to preceding petrodiesel exposure studies. The present findings, together with the recently reported adverse cardiovascular effects after similar biodiesel exposure, indicate that biodiesel is not free of toxicity and may affect human health.

Background: A novel concept of controlled, short-duration supramaximal HIIT enables 3-4 times higher exercise intensities with reduced dyspnea, compared to moderate-intensity continuous training (MICT) in people with COPD. However, its effects on neurotrophic factors and brain health are yet to be investigated. We aimed to examine the acute response of neurotrophic factors to supramaximal HIIT and MICT in people with COPD.

Methods: Sixteen people with mild to severe COPD (75±6 years; 73±13 FEV1%pred) underwent supramaximal HIIT (comprising 10x6 sec intervals interspersed with 54 sec rest) and MICT (20 min at 60% CPET Wpeak). Supramaximal HIIT was performed at two intensities (HIIT60% and HIIT80%). We measured plasma levels of brain-derived neurotrophic factor (BDNF), irisin, cathepsin B and clusterin pre- and post- exercise.

Results: BDNF increased after both HIIT and MICT (Fig 1). Clusterin increased during HIIT80% (19940 [−35900 to 49600] ng/mL, +11%, p=0.01) and MICT (23390 [−5060 to 51010] ng/mL, +12%, p=0.03), but not HIIT60% (−1100 [−10060 to 113600] ng/mL, -1%, p=0.85). No changes were seen in irisin or cathepsin B.

Conclusion: For the first time, we showed that in COPD, supramaximal HIIT induces a similar increase in BDNF as MICT, with half the exercise duration. Supramaximal HIIT might be a viable exercise modality in COPD, while its long-term effects on brain health remain to be investigated.

Background: Beyond being a pulmonary disease, chronic obstructive pulmonary disease (COPD) presents with extrapulmonary manifestations including reduced cognitive, cardiovascular, and muscle function. While exercise training is the cornerstone in the non-pharmacological treatment of COPD, there is a need for new exercise training methods due to suboptimal adaptations when following traditional exercise guidelines, often applying moderate-intensity continuous training (MICT). In people with COPD, short-duration high-intensity interval training (HIIT) holds the potential to induce a more optimal stimulus for training adaptations while circumventing the ventilatory burden often associated with MICT in people with COPD. We aim to determine the effects of supramaximal HIIT and MICT on extrapulmonary manifestations in people with COPD compared to matched healthy controls.

Methods: COPD-HIIT is a prospective, multi-centre, randomized, controlled trial with blinded assessors and data analysts, employing a parallel-group designed trial. In phase 1, we will investigate the effects and mechanisms of a 12-week intervention of supramaximal HIIT compared to MICT in people with COPD (n = 92) and matched healthy controls (n = 70). Participants will perform watt-based cycling two to three times weekly. In phase 2, we will determine how exercise training and inflammation impact the trajectories of neurodegeneration, in people with COPD, over 24 months. In addition to the 92 participants with COPD performing HIIT or MICT, a usual care group (n = 46) is included in phase 2. In both phases, the primary outcomes are a change from baseline in cognitive function, cardiorespiratory fitness, and muscle power. Key secondary outcomes include change from baseline exercise tolerance, brain structure, and function measured by MRI, neuroinflammation measured by PET/CT, systemic inflammation, and intramuscular adaptations. Feasibility of the interventions will be comprehensively investigated.

Discussion: The COPD-HIIT trial will determine the effects of supramaximal HIIT compared to MICT in people with COPD and healthy controls. We will provide evidence for a novel exercise modality that might overcome the barriers associated with MICT in people with COPD. We will also shed light on the impact of exercise at different intensities to reduce neurodegeneration. The goal of the COPD-HIIT trial is to improve the treatment of extrapulmonary manifestations of the disease.

The aim of this study was to investigate the relationship between source-specific ambient particulate air pollution concentrations and the incidence of dementia. The study encompassed 70,057 participants from the Västerbotten intervention program cohort in Northern Sweden with a median age of 40 years at baseline. High-resolution dispersion models were employed to estimate source-specific particulate matter (PM) concentrations, such as PM10 and PM2.5 from traffic, exhaust, and biomass (mainly wood) burning, at the residential addresses of each participant. Cox regression models, adjusted for potential confounding factors, were used for the assessment. Over 884,847 person-years of follow-up, 409 incident dementia cases, identified through national registers, were observed. The study population’s average exposure to annual mean total PM10 and PM2.5 lag 1–5 years was 9.50 µg/m3 and 5.61 µg/m3, respectively. Increased risks were identified for PM10-Traffic (35% [95% CI 0–82%]) and PM2.5-Exhaust (33% [95% CI − 2 to 79%]) in the second exposure tertile for lag 1–5 years, although no such risks were observed in the third tertile. Interestingly, a negative association was observed between PM2.5-Wood burning and the risk of dementia. In summary, this register-based study did not conclusively establish a strong association between air pollution exposure and the incidence of dementia. While some evidence indicated elevated risks for PM10-Traffic and PM2.5-Exhaust, and conversely, a negative association for PM2.5-Wood burning, no clear exposure–response relationships were evident.

In urban areas, inhalation of fine particles from combustion sources such as diesel engines causes adverse health effects. For toxicity testing, a substantial amount of particulate matter (PM) is needed. Conventional sampling involves collection of PM onto substrates by filtration or inertial impaction. A major drawback to those methodologies is that the extraction process can modify the collected particles and alter their chemical composition. Moreover, prior to toxicity testing, PM samples need to be resuspended, which can alter the PM sample even further. Lastly, the choice of the resuspension medium may also impact the detected toxicological responses. In this study, we compared the toxicity profile of PM obtained from two alternative sampling systems, using in vitro toxicity assays. One system makes use of condensational growth before collection in water in an impinger – BioSampler (CG-BioSampler), and the other, a Dekati® Gravimetric Impactor (DGI), is based on inertial impaction. In addition, various methods for resuspension of DGI collected PM were compared. Tested endpoints included cytotoxicity, formation of cellular reactive oxygen species, and genotoxicity. The alternative collection and suspension methods affected different toxicological endpoints. The water/dimethyl sulfoxide mixture and cell culture medium resuspended particles, along with the CG-BioSampler sample, produced the strongest responses. The water resuspended sample from the DGI appeared least toxic. CG-BioSampler collected PM caused a clear increased response in apoptotic cell death. We conclude that the CG-BioSampler PM sampler is a promising alternative to inertial impaction sampling.

Introduction: Resistance training (RT) is a key component of pulmonary rehabilitation for people with COPD; however, whether the effects of RT could be optimized by utilizing the exercise principle of non-linear periodization is yet to be determined.

Method: An international multicenter RCT was conducted across three countries. Fifty-seven people with COPD (70+7 yrs, FEV1% 49+21, 58% male) were randomized to 8 weeks of RT designed per current COPD guidelines to improve muscle strength or to non-linear periodized resistance training (NLPRT) designed to improve muscle strength [4 weeks] but also muscle endurance [4 weeks]. Outcomes included muscle strength, muscle endurance, functional exercise capacity (1-minute sit-to-stand [1-STS], endurance shuttle walk test [ESWT], Unsupported Upper Limb Exercise test [UULEX]), and disease-specific quality of life (QoL). Intention-to-treat (ITT) analysis was utilized, and Cohen's D Effect Sizes [ES] were calculated.

Result: ITT analysis demonstrated that NLPRT resulted in more pronounced effects on muscle strength (+33% vs. +21%, ES 0.928), muscle endurance (+147% vs. +50%, ES 1.080), ESWT (+168m vs. +36m, ES 0.592), 1-STS (+4 STS vs. 1 STS, ES 0.864), UULEX (+142sec vs. + 42sec, ES=0.819) (all p<0.05) when compared to RT. Both NLPRT and RT resulted in clinically relevant improvements in QoL without differences between modalities.

Conclusion: These results indicate that 8 weeks of NLPRT yields significantly better outcomes in various dimensions of muscle function and functional capacity when compared to 8 weeks of traditional RT. Consequently, this suggests a potential need for reevaluating and updating current RT guidelines to incorporate these findings.

The use of alternative diesel fuels has increased due to the demand for renewable energy sources. There is limited knowledge regarding the potential health effects caused by exhaust emissions from biodiesel- and renewable diesel-fueled engines. This study investigates the toxic effects of particulate matter (PM) emissions from a diesel engine powered by conventional petroleum diesel fuel (SD10) and two biodiesel and renewable diesel fuels in vitro. The fuels used were rapeseed methyl ester (RME), soy methyl ester (SME), and Hydrogenated Vegetable Oil (HVO), either pure or as 50% blends with SD10. Additionally, a 5% RME blend was also used. The highest concentration of polycyclic aromatic hydrocarbon emissions and elemental carbon (EC) was found in conventional diesel and the 5% RME blend. HVO PM samples also exhibited a high amount of EC. A dose-dependent genotoxic response was detected with PM from SD10, pure SME, and RME as well as their blends. Reactive oxygen species levels were several times higher in cells exposed to PM from SD10, pure HVO, and especially the 5% RME blend. Apoptotic cell death was observed in cells exposed to PM from SD10, 5% RME blend, the 50% SME blend, and HVO samples. In conclusion, all diesel PM samples, including biodiesel and renewable diesel fuels, exhibited toxicity.