Although murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin, the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration, fibrosis and severe functional deficit comparable to that of DMD limb muscle, although adult mice show no overt respiratory impairment. Progressive functional changes include reductions in strength (to 13.5% of control by two years of age), elasticity, twitch speed and fibre length. The collagen density rises to at least seven times that of control diaphragm and ten times that of mdx hind-limb muscle. By 1.5 years of age, similar but less severe histological changes emerge in the accessory muscles of respiration. On the basis of these findings, we propose that dystrophin deficiency alters the threshold for work-induced injury. Our data provide a quantitative framework for studying the pathogenesis of dystrophy and extend the application of the mdx mouse as an animal model.

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Background Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects. Objective National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies. Methods We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health–organized workshop convened in March 2010 and finalized in September 2011. Results Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures. Conclusion The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories.

Asthma is characterized by airway inflammation, remodeling, and hyperresponsiveness to contractile stimuli that promote airway constriction and wheezing. Here we present evidence that sphingosine 1-phosphate (SPP) is a potentially important inflammatory mediator implicated in the pathogenesis of airway inflammation and asthma. SPP levels were elevated in the airways of asthmatic (but not control) subjects following segmental antigen challenge, and this increase was correlated with a concomitant increase in airway inflammation. Because human airway smooth muscle (ASM) cells expressed EDG receptors for SPP , we examined whether SPP may play a role in airway inflammation and remodeling, by affecting ASM cell growth, contraction, and cytokine secretion. SPP is mitogenic and augments EGF-and thrombininduced DNA proliferation by increasing G 1 /S progression. SPP increased phosphoinositide turnover and intracellular calcium mobilization, the acute signaling events that affect ASM contraction. By modulating adenylate cyclase activity and cAMP accumulation, SPP had potent effects on cytokine secretion. Although SPP inhibited TNF-α-induced RANTES release, it induced substantial IL-6 secretion alone and augmented production of IL-6 induced by TNF-α. These studies are the first to associate SPP with airway inflammation and to identify SPP as an effective regulator of ASM growth, contraction and synthetic functions.Key words: cAMP • EDG receptors • cytokines • mitogenesis • cytosolic calcium sthma, a common chronic disease, is characterized by airway hyper-responsiveness and reversible airflow obstruction. Exposure to environmental antigen, a frequent trigger of acute asthmatic attacks, induces an inflammatory reaction in the airway characterized in part by an influx of lymphocytes and eosinophils that secrete various agents capable of A perpetuating inflammation and provoking airway smooth muscle (ASM) contraction. Accordingly, the majority of therapeutic agents in asthma seek to minimize the development or consequences of airway inflammation or directly promote ASM relaxation.Recently, a more chronic feature of asthma, termed "airway remodeling", has drawn the attention of asthma research. Airway remodeling refers to structural alterations in the bronchial wall characterized by ASM hypertrophy and hyperplasia, epithelial denudation, mucus gland hyperplasia, lamina recticularis thickening, and vasculogenesis. The functional consequence of these histological findings is to render the airway irreversibly obstructed in some susceptible asthmatics. Others (1-4) and we (5) have recently suggested a prominent role for ASM in orchestrating both the acute inflammatory reaction and the chronic features of airway remodeling that occur in asthma. This assertion is supported by observations that ASM mass is increased in the bronchi of severe chronic asthmatics (6), that numerous agents that are elevated in the asthmatic airway are mitogenic to ASM in vitro (5), and that ASM expresses adhesion molecules (7) and secretes numerous cytokin...

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