Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell-mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.innate response | cytokine | therapy | inflammation

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Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging. The primary goal of the current study was to empirically evaluate the independent relationships between physical activity and fitness with functional brain health among healthy older adults, as measured by the functional connectivity of cognitively and clinically relevant resting state networks. To build context for fitness and physical activity associations in older adults, we first demonstrate that young adults have greater within-network functional connectivity across a broad range of cortical association networks. Based on these results and previous research, we predicted that individual differences in fitness and physical activity would be most strongly associated with functional integrity of the networks most sensitive to aging. Consistent with this prediction, and extending on previous research, we showed that cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline, and effects were strongest in the Default Mode Network (DMN). Furthermore, our results suggest that the positive association of fitness with brain function can occur independent of habitual physical activity. Overall, our findings provide further support that cardiorespiratory fitness is an important factor in moderating the adverse effects of aging on cognitively and clinically relevant functional brain networks.

BackgroundCystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation.MethodsBlood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR.ResultsCF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF.ConclusionsCF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.

Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with better cognitive function in late life, but the neural correlates for these relationships are unclear. To study these correlates, we examined the association of both PA and CRF with measures of white matter (WM) integrity in 88 healthy low-fit adults (age 60–78). Using accelerometry, we objectively measured sedentary behavior, light PA, and moderate to vigorous PA (MV-PA) over a week. We showed that greater MV-PA was related to lower volume of WM lesions. The association between PA and WM microstructural integrity (measured with diffusion tensor imaging) was region-specific: light PA was related to temporal WM, while sedentary behavior was associated with lower integrity in the parahippocampal WM. Our findings highlight that engaging in PA of various intensity in parallel with avoiding sedentariness are important in maintaining WM health in older age, supporting public health recommendations that emphasize the importance of active lifestyle.

This study reveals the crucial role of defective TLR3 function in promoting progressive IPF.

Introduction Recent attention has highlighted the importance of reducing sedentary time for maintaining health and quality of life. However, it is unclear how changing sedentary behavior may influence executive functions and self-regulatory strategy use, which are vital for the long-term maintenance of a health behavior regimen. The purpose of this cross-sectional study is to examine the estimated self-regulatory and executive functioning effects of substituting 30 minutes of sedentary behavior with 30 minutes of light activity, moderate-to-vigorous physical activity (MVPA), or sleep in a sample of older adults. Methods This study reports baseline data collected from low-active healthy older adults (N = 247, mean age 65.4±4.6 years) recruited to participate in a six month randomized controlled exercise trial examining the effects of various modes of exercise on brain health and function. Each participant completed assessments of physical activity self-regulatory strategy use (i.e., self-monitoring, goal-setting, social support, reinforcement, time management, and relapse prevention) and executive functioning. Physical activity and sedentary behaviors were measured using accelerometers during waking hours for seven consecutive days at each time point. Isotemporal substitution analyses were conducted to examine the effect on self-regulation and executive functioning should an individual substitute sedentary time with light activity, MVPA, or sleep. Results The substitution of sedentary time with both sleep and MVPA influenced both self-regulatory strategy use and executive functioning. Sleep was associated with greater self-monitoring (B = .23, p = .02), goal-setting (B = .32, p < .01), and social support (B = .18, p = .01) behaviors. Substitution of sedentary time with MVPA was associated with higher accuracy on 2-item (B = .03, p = .01) and 3-item (B = .02, p = .04) spatial working memory tasks, and with faster reaction times on single (B = −23.12, p = .03) and mixed-repeated task-switching blocks (B = −27.06, p = .04). Substitution of sedentary time with sleep was associated with marginally faster reaction time on mixed-repeated task-switching blocks (B = − 12.20, p = .07) and faster reaction time on mixed-switch blocks (B = 17.21, p = .05), as well as reduced global reaction time switch cost (B = −16.86, p = .01). Substitution for light intensity physical activity did not produce significant effects. Conclusions By replacing sedentary time with sleep and MVPA, individuals may bolster several important domains of self-regulatory behavior and executive functioning. This has important implications for the design of long-lasting health behavior interventions.

Context: Declarative memory largely depends upon normal functioning temporal lobes (hippocampal complex) and prefrontal cortex. Animal studies suggest abnormal hippocampal function in hypothyroidism.Objective: The aim of the study was to assess declarative memory in overt and subclinical (SCH) hypothyroid patients before and after L-T 4 (LT4) replacement and in matched normal subjects. Design and Setting:A prospective, open-labeled interventional study was conducted at a teaching hospital.Participants and Intervention: Hypothyroid (n ϭ 21) and SCH (n ϭ 17) patients underwent neuropsychological tests at baseline and 3 and 6 months after LT4 replacement. Normal subjects were studied at the same time-points.Main Outcome: Tests of spatial, verbal, associative, and working memory; attention; and response inhibition and the Hospital Anxiety and Depression Scale were administered.Results: Baseline deficits in spatial, associative, and verbal memory, which rely upon the integrity of the hippocampal and frontal areas, were identified in patients with overt hypothyroidism. Spatial and verbal memory were impaired in SCH patients (P Ͻ 0.05). TSH levels correlated negatively (P Ͻ 0.05) with these deficits. After LT4 replacement, verbal memory normalized. Spatial memory normalized in the SCH group but remained impaired in the hypothyroid group. Associative memory deficits persisted in the overt hypothyroid group. Hospital Anxiety and Depression Scale scores did not correlate with cognitive function. Measures of attention and response inhibition did not differ from control subjects. Conclusion:Cognitive impairment occurs in SCH and more markedly in overt hypothyroidism. These impairments appear predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing. We propose that these deficits may reflect an underlying disruption of normal hippocampal function and/or connectivity. (J Clin Endocrinol Metab 94: 3789 -3797, 2009) A lthough impairment of cognitive function in overt hypothyroidism has been recognized for more than a century, the nature and severity of this impairment and the degree of recovery after treatment remain unclear (1).Some studies have reported general cognitive slowing (2, 3), whereas others suggest a more specific mnemonic deficit (4, 5). Deficits in hippocampal-dependent memory tasks (6) that are reversible with thyroid hormone replace-