Cigarette smoking induced decrease in fibronectin and COL1A1 in locomotor muscle in a guinea pig COPD model

Background: Sarcopenia is a major comorbidity in patients with chronic obstructive pulmonary disease (COPD) caused by decreased physical activity capacity, cigarette smoke (CS) and chronic hypoxia (CH). These risk factors affect muscle anabolic and catabolic biomarkers responsible for sarcopenia. However, whether CS and CH affect muscle extracellular matrix (ECM) biomarkers is still unknown. Intramuscular ECM plays an important role in muscle growth and repair processes, but their role in sarcopenia is under investigated. The aim of this study was to investigate alterations in the expression of intramuscular ECMs biomarkers in response to CH and CS. We hypothesize that altered expression of the ECM molecules promoted by CH and CS contribute to development of sarcopenia. Methods: Skeletal muscle from a guinea pig animal model exposed (a) to 12 weeks CS (CS group), (b) to 10-week normal atmospheric air followed by 2-week of inspiratory oxygen fraction (FI,O2) of 0.12 in a hypoxic chamber (CH group), (c) to 12-week CS followed by 2-week CH (CS-CH group), (d) to 12-week sham CS followed by 2-week normal atmospheric air (Control group) were analysed by Real-time PCR for the change in expression of intramuscular ECM biomarkers. Results: Only CS treatment induced significant decreased in fibronectin and COLA1 transcriptomes by 43 (p=0.05) and by 84.1 (p=0.026) respectively, compared to controls. CH and CS-CH treatment downregulated fibronectin and COLA1, but not significantly compared to controls. No significant differences in ECM gene expression were observed when comparing CH with CS treatment.Conclusion: CS affects ECM composition altering the expression of fibronectin and COL1A1. The role of ECM biomarkers to muscle sarcopenia is being investigated

Menstrual cycle-associated modulations in neuromuscular function and fatigability of the knee extensors in eumenorrheic women

Sex hormone concentrations of eumenorrheic women typically fluctuate across the menstrual cycle and can affect neural function such that estrogen has neuroexcitatory effects, and progesterone induces inhibition. However, the effects of these changes on corticospinal and intracortical circuitry and the motor performance of the knee extensors are unknown. The present two-part investigation aimed to 1) determine the measurement error of an exercise task, transcranial magnetic stimulation (TMS)-, and motor nerve stimulation (MNS)-derived responses in women ingesting a monophasic oral contraceptive pill (hormonally-constant) and 2) investigate whether these measures were modulated by menstrual cycle phase (MCP), by examining them before and after an intermittent isometric fatiguing task (60% of maximal voluntary contraction, MVC) with the knee extensors until task failure in eumenorrheic women on days 2, 14, and 21 of the menstrual cycle. The repeatability of neuromuscular measures at baseline and fatigability ranged between moderate and excellent in women taking the oral contraceptive pill. MVC was not affected by MCP (P = 0.790). Voluntary activation (MNS and TMS) peaked on day 14 (P = 0.007 and 0.008, respectively). Whereas corticospinal excitability was unchanged, short-interval intracortical inhibition was greatest on day 21 compared with days 14 and 2 (P < 0.001). Additionally, time to task failure was longer on day 21 than on both days 14 and 2 (24 and 36%, respectively, P = 0.030). The observed changes were larger than the associated measurement errors. These data demonstrate that neuromuscular function and fatigability of the knee extensors vary across the menstrual cycle and may influence exercise performance involving locomotor muscles. NEW & NOTEWORTHY The present two-part study first demonstrated the repeatability of transcranial magnetic stimulation- and electrical motor nerve stimulation-evoked variables in a hormonally constant female population. Subsequently, it was demonstrated that the eumenorrheic menstrual cycle affects neuromuscular function. Changing concentrations of neuroactive hormones corresponded to greater voluntary activation on day 14, greater intracortical inhibition on day 21, and lowest fatigability on day 21. These alterations of knee extensor neuromuscular function have implications for locomotor activities

Osteopontin Promotes Protective Antigenic Tolerance against Experimental Allergic Airway Disease

In the context of inflammation, osteopontin (Opn) is known to promote effector responses, facilitating a proinflammatory environment; however, its role during antigenic tolerance induction is unknown. Using a mouse model of asthma, we investigated the role of Opn during antigenic tolerance induction and its effects on associated regulatory cellular populations prior to disease initiation. Our experiments demonstrate that Opn drives protective antigenic tolerance by inducing accumulation of IFN-β–producing plasmacytoid dendritic cells, as well as regulatory T cells, in mediastinal lymph nodes. We also show that, in the absence of TLR triggers, recombinant Opn, and particularly its SLAYGLR motif, directly induces IFN-β expression in Ag-primed plasmacytoid dendritic cells, which renders them extra protective against induction of allergic airway disease upon transfer into recipient mice. Lastly, we show that blockade of type I IFNR prevents antigenic tolerance induction against experimental allergic asthma. Overall, we unveil a new role for Opn in setting up a tolerogenic milieu boosting antigenic tolerance induction, thus leading to prevention of allergic airway inflammation. Our results provide insight for the future design of immunotherapies against allergic asthma

Can muscle protein metabolism be specifically targeted by exercise training in COPD?

Patients with stable chronic obstructive pulmonary disease (COPD) frequently exhibit unintentional accentuated peripheral muscle loss and dysfunction. Skeletal muscle mass in these patients is a strong independent predictor of morbidity and mortality. Factors including protein anabolism/catabolism imbalance, hypoxia, physical inactivity, inflammation, and oxidative stress are involved in the initiation and progression of muscle wasting in these patients. Exercise training remains the most powerful intervention for reversing, in part, muscle wasting in COPD. Independently of the status of systemic or local muscle inflammation, rehabilitative exercise training induces up-regulation of key factors governing skeletal muscle hypertrophy and regeneration. However, COPD patients presenting similar degrees of lung dysfunction do not respond alike to a given rehabilitative exercise stimulus. In addition, a proportion of patients experience limited clinical outcomes, even when exercise training has been adequately performed. Consistently, several reports provide evidence that the muscles of COPD patients present training-induced myogenic activity resistance as exercise training induces a limited number of differentially expressed genes, which are mostly associated with protein degradation. This review summarises the nature of muscle adaptations induced by exercise training, promoted both by changes in the expression of contractile proteins and their function typically controlled by intracellular signalling and transcriptional responses. Rehabilitative exercise training in COPD patients induces skeletal muscle mechanosensitive signalling pathways for protein accretion and its regulation during muscle contraction. Exercise training also induces synthesis of myogenic proteins by which COPD skeletal muscle promotes hypertrophy leading to fusion of myogenic cells to the myofibre. Understanding of the biological mechanisms that regulate exercise training-induced muscle growth and regeneration is necessary for implementing therapeutic strategies specifically targeting myogenesis and hypertrophy in these patients

An integrin axis induces IFN-β production in plasmacytoid dendritic cells

Type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) has been mainly studied in the context of Toll-like receptor (TLR) activation. In the current report, we reveal that, in the absence of TLR activation, the integrin-binding SLAYGLR motif of secreted osteopontin (sOpn) induces IFN-β production in murine pDCs. This process is mediated by α4β1 integrin, indicating that integrin triggering may act as a subtle danger signal leading to IFN-β induction. The SLAYGLR-mediated α4 integrin/IFN-β axis is MyD88 independent and operates via a PI3K/mTOR/IRF3 pathway. Consequently, SLAYGLR-treated pDCs produce increased levels of type I IFNs following TLR stimulation. Intratumoral administration of SLAYGLR induces accumulation of IFN-β–expressing pDCs and efficiently suppresses melanoma tumor growth. In this process, pDCs are crucial. Finally, SLAYGLR enhances pDC development from bone marrow progenitors. These findings open new questions on the roles of sOpn and integrin α4 during homeostasis and inflammation. The newly identified integrin/IFN-β axis may be implicated in a wide array of immune responses

Soluble guanylyl cyclase expression is reduced in allergic asthma

Soluble guanylyl cyclase (sGC) is an enzyme highly expressed in the lung that generates cGMP contributing to airway smooth muscle relaxation. To determine whether the bronchoconstriction observed in asthma is accompanied by changes in sGC expression, we used a well-established murine model of allergic asthma. Histological and biochemical analyses confirmed the presence of inflammation in the lungs of mice sensitized and challenged with ovalbumin (OVA). Moreover, mice sensitized and challenged with OVA exhibited airway hyperreactivity to methacholine inhalation. Steady-state mRNA levels for all sGC subunits (α1, α2, and β1) were reduced in the lungs of mice with allergic asthma by 60–80%, as estimated by real-time PCR. These changes in mRNA were paralleled by changes at the protein level: α1, α2, and β1 expression was reduced by 50–80% as determined by Western blotting. Reduced α1 and β1 expression in bronchial smooth muscle cells was demonstrated by immunohistochemistry. To study if sGC inhibition mimics the airway hyperreactivity seen in asthma, we treated naïve mice with a selective sGC inhibitor. Indeed, in mice receiving ODQ the methacholine dose response was shifted to the left. We conclude that sGC expression is reduced in experimental asthma contributing to the observed airway hyperreactivity

Down regulation of soluble guanylate cyclase contributes to bronchial hyperreactivity in asthma

We have used an ovalbumin (OVA) model of inflammatory airway disease to explore the role of soluble guanylyl cyclase (sGC) in bronchial hyperactivity (BHR) and inflammation associated with asthma. OVA treated mice exhibited a 60-80 % reduction in steady-state mRNA levels of sGC subunits compared to control mice as determined by real-time PCR. Similarly, protein levels of the sGC subunits were reduced by 50-70% in animals with asthma. In addition, inhibition of sGC activity using the selective inhibitor 1H-[1,2,4] oxydiazolo[4,3-ea]quinoxalin-1-one (ODQ) lead to increased basal bronchial tone and airway reactivity to methacholine. ODQ-treated mice, also exhibited a significant increase in macrophage number in the bronchiolar lavage (BAL) that was not accompanied by changes in lung histology and interleukin-13 production. These data indicate that sGC inhibition is accompanied by an inflammatory response that is qualitatively different from that observed in asthma (eosinophil infiltration and increased IL-13 production). We conclude that sGC inhibition contributes to the BHR seen in asthma

Angiopoietin-1 Protects against Airway Inflammation and Hyperreactivity in Asthma

Rationale: The angiopoietins (Ang) comprise a family of growth factors mainly known for their role in blood vessel formation and remodeling. The best-studied member, Ang-1, exhibits antiapoptotic and antiinflammatory effects. Although the involvement of Ang-1 in angiogenesis is well recognized, little information exists about its role in respiratory physiology and disease. On the basis of its ability to inhibit vascular permeability, adhesion molecule expression, and cytokine production, we hypothesized that Ang-1 administration might exert a protective role in asthma. Objectives: To determine changes in the expression of Ang and to assess the ability of Ang-1 to prevent the histologic, biochemical, and functional changes observed in an animal model of asthma. Methods: To test our hypothesis, a model of allergic airway disease that develops after ovalbumin (OVA) sensitization and challenge was used. Measurements and Main Results: Ang-1 expression was reduced at the mRNA and protein levels in lung tissue of mice sensitized and challenged with OVA, leading to reduced Tie2 phosphorylation. Intranasal Ang-1 treatment prevented the OVA-induced eosinophilic lung infiltration, attenuated the increase in IL-5 and IL-13, and reduced eotaxin and vascular cell adhesion molecule 1 expression. These antiinflammatory actions of Ang-1 coincided with higher levels of IκB and decreased nuclear factor-κB binding activity. More importantly, Ang-1 reversed the OVA-induced increase in tissue resistance and elastance, improving lung function. Conclusions: We conclude that Ang-1 levels are decreased in asthma and that administration of Ang-1 might be of therapeutic value because it prevents the increased responsiveness of the airways to constrictors and ameliorates inflammation

Breath Markers of Oxidative Stress and Airway Inflammation in Seasonal Allergic Rhinitis

Oxidative stress (OS) is well documented in asthma, but so far little data has been reported in non-asthmatic patients with Seasonal Allergic Rhinitis (SAR). The aim of this study is to investigate the degree of OS and airway inflammation in patients with SAR, with and without concomitant Asthma (SAR +A), using breath markers in exhaled air and in Exhaled Breath Condensate (EBC). In addition, the effects of natural allergen exposure and intranasal steroid treatment on these markers were evaluated. Exhaled NO (eNO) and CO, combined with measurements of 8-Isoprostane (Iso-8), Leukotriene B4 (LTB4) and nitrate/nitrite in EBC, were performed in 23 patients, 11 with SAR and 12 with SAR+A, and 16 healthy subjects. Iso-8 and LTB4 were significantly increased in both groups of patients (median values 43.6 pg/ml and 138.4 pg/ml in SAR group; 38.9 pg/ml, and 164.6 pg/ml in SAR+A group respectively; p>0.05) compared to healthy subjects (18.6 pg/ml and 7.8 pg/ml; p0.05). Nasal steroids caused significant reduction in LTB4 and 8-isoprostane levels in both groups of patients (p<0.05), while nitrate levels and eNO concentration were little affected by nasal treatment. OS markers were decreased at normal levels out of pollen season. Natural allergen exposure induces OS and airway inflammation, as assessed by measurements of markers in EBC and exhaled air, in patients with SAR who have no clinical signs of lower airway involvement. Besides, intranasal steroid treatment may have a regulatory role in the OS

Osteopontin Deficiency Protects against Airway Remodeling and Hyperresponsiveness in Chronic Asthma

Rationale: Osteopontin (OPN) is a cytokine that is upregulated in epithelial cells and macrophages in the lungs of mice during chronic allergen challenge and airway remodeling and also in lungs of patients with asthma. However, it remains unclear whether OPN has an in vivo effect on lung remodeling in allergic asthma. Based on its ability to induce smooth muscle and fibroblast proliferation and migration we hypothesize that OPN regulates lung remodeling and also affects subsequent airway hyperresponsiveness (AHR). Objectives: Study the role of OPN in airway remodeling using OPN-knockout (KO) mice and a reversal approach administering recombinant mouse OPN (rOPN) in KO mice before challenge. Methods: A chronic allergen-challenge model of airway remodeling with OPN KO mice, KO mice treated with rOPN, and human bronchial smooth muscle were used. Measurements and Main Results: OPN deficiency protected mice against ova-induced AHR, which was associated with lower collagen and mucus production, gob-5 mRNA expression, submucosal cell area infiltration, and proliferation. Administration of rOPN to KO mice, just at the final five allergen challenges, exacerbated AHR and all the remodeling characteristics measured. In addition, rOPN increased the expression of IL-13 and pro–matrix metalloproteinase-9 in the lungs. Moreover, we demonstrated that rOPN induces proliferation of human BSM through binding to its αvβ3 integrin receptor and activation of PI3K/Akt downstream signaling pathway. Conclusions: We conclude that OPN deficiency protects against remodeling and AHR. Thus our data reveal OPN as a novel therapeutic target for airway remodeling and associated AHR in chronic asthma