Mesenchymal cell survival in airway and interstitial pulmonary fibrosis

Fibrotic reactions in the airways of the lung or the pulmonary interstitium are a common pathologic outcome after exposure to a wide variety of toxic agents, including metals, particles or fibers. The survival of mesenchymal cells (fibroblasts and myofibroblasts) is a key factor in determining whether a fibroproliferative response that occurs after toxic injury to the lung will ultimately resolve or progress to a pathologic state. Several polypeptide growth factors, including members of the platelet-derived growth factor (PDGF) family and the epidermal growth factor (EGF) family, are prosurvival factors that stimulate a replicative and migratory mesenchymal cell phenotype during the early stages of lung fibrogenesis. This replicative phenotype can progress to a matrix synthetic phenotype in the presence of transforming growth factor-β1 (TGF-β1). The resolution of a fibrotic response requires growth arrest and apoptosis of mesenchymal cells, whereas progressive chronic fibrosis has been associated with mesenchymal cell resistance to apoptosis. Mesenchymal cell survival or apoptosis is further influenced by cytokines secreted during Th1 inflammation (e.g., IFN-γ) or Th2 inflammation (e.g., IL-13) that modulate the expression of growth factor activity through the STAT family of transcription factors. Understanding the mechanisms that regulate the survival or death of mesenchymal cells is central to ultimately developing therapeutic strategies for lung fibrosis

The 2014 ALMA Long Baseline Campaign: An Overview

A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to ~15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from September to late November 2014, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at ~350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy

Pathogenesis of Molar Hypomineralisation: Hypomineralised 6-Year Molars Contain Traces of Fetal Serum Albumin

Molar Hypomineralisation (MH) is gaining cross-sector attention as a global health problem, making deeper enquiry into its prevention a research priority. However, causation and pathogenesis of MH remain unclear despite 100 years of investigation into "chalky" dental enamel. Contradicting aetiological dogma involving disrupted enamel-forming cells (ameloblasts), our earlier biochemical analysis of chalky enamel opacities implicated extracellular serum albumin in enamel hypomineralisation. This study sought evidence that the albumin found in chalky enamel reflected causal events during enamel development rather than later association with pre-existing enamel porosity. Hypothesising that blood-derived albumin infiltrates immature enamel and directly blocks its hardening, we developed a "molecular timestamping" method that quantifies the adult and fetal isoforms of serum albumin ratiometrically. Applying this novel approach to 6-year molars, both isoforms of albumin were detectable in 6 of 8 chalky opacities examined (corresponding to 4 of 5 cases), indicating developmental acquisition during early infancy. Addressing protein survival, in vitro analysis showed that, like adult albumin, the fetal isoform (alpha-fetoprotein) bound hydroxyapatite avidly and was resistant to kallikrein-4, the pivotal protease involved in enamel hardening. These results shift primary attention from ameloblast injury and indicate instead that an extracellular mechanism involving localised exposure of immature enamel to serum albumin constitutes the crux of MH pathogenesis. Together, our pathomechanistic findings plus the biomarker approach for onset timing open a new direction for aetiological investigations into the medical prevention of MH

A Breakthrough in Understanding the Pathogenesis of Molar Hypomineralisation: The Mineralisation-Poisoning Model

Popularly known as "chalky teeth", molar hypomineralisation (MH) affects over 1-in-5 children worldwide, triggering massive amounts of suffering from toothache and rapid decay. MH stems from childhood illness and so offers a medical-prevention avenue for improving oral and paediatric health. With a cross-sector translational research and education network (The D3 Group; thed3group.org) now highlighting this global health opportunity, aetiological understanding is urgently needed to enable better awareness, management and eventual prevention of MH. Causation and pathogenesis of "chalky enamel spots" (i.e., demarcated opacities, the defining pathology of MH) remain unclear despite 100 years of investigation. However, recent biochemical studies provided a pathomechanistic breakthrough by explaining several hallmarks of chalky opacities for the first time. This article outlines these findings in context of previous understanding and provides a working model for future investigations. The proposed pathomechanism, termed "mineralisation poisoning", involves localised exposure of immature enamel to serum albumin. Albumin binds to enamel-mineral crystals and blocks their growth, leading to chalky opacities with distinct borders. Being centred on extracellular fluid rather than enamel-forming cells as held by dogma, this localising pathomechanism invokes a new type of connection with childhood illness. These advances open a novel direction for research into pathogenesis and causation of MH, and offer prospects for better clinical management. Future research will require wide-ranging inputs that ideally should be coordinated through a worldwide translational network. We hope this breakthrough will ultimately lead to medical prevention of MH, prompting global health benefits including major reductions in childhood tooth decay

Surface Integrity governs the proteome of hypomineralised MJ

Growing interest in the treatment and prevention of Molar/Incisor Hypomineralization (MIH) warrants investigation into the protein composition of hypomineralized enamel. Hypothesizing abnormality akin to amelogenesis imperfecta, we profiled proteins in hypomineralized enamel from human permanent first molars using a biochemical approach. Hypomineralized enamel was found to have from 3- to 15-fold higher protein content than normal, but a near-normal level of residual amelogenins. This distinguished MIH from hypomaturation defects with high residual amelo- genins (amelogenesis imperfecta, fluorosis) and so typified it as a hypocalcification defect. Second, hypo- mineralized enamel was found to have accumulated various proteins from oral fluid and blood, with dif- ferential incorporation depending on integrity of the enamel surface. Pathogenically, these results point to a pre-eruptive disturbance of mineralization involving albumin and, in cases with post-eruptive breakdown, subsequent protein adsorption on the exposed hydroxy- apatite matrix. These insights into the pathogenesis and properties of hypomineralized enamel hold significance for prevention and treatment of MIH

Molar Hypomineralisation: A Call to Arms for Enamel Researchers

Developmental dental defects (DDDs, hereafter "D3s") hold significance for scientists and practitioners from both medicine and dentistry. Although, attention has classically dwelt on three other D3s (amelogenesis imperfecta, dental fluorosis, and enamel hypoplasia), dental interest has recently swung toward Molar Hypomineralisation (MH), a prevalent condition characterised by well-delineated ("demarcated") opacities in enamel. MH imposes a significant burden on global health and has potential to become medically preventable, being linked to infantile illness. Yet even in medico-dental research communities there is only narrow awareness of this childhood problem and its link to tooth decay, and of allied research opportunities. Major knowledge gaps exist at population, case and tooth levels and salient information from enamel researchers has sometimes been omitted from clinically-oriented conclusions. From our perspective, a cross-sector translational approach is required to address these complex inadequacies effectively, with the ultimate aim of prevention. Drawing on experience with a translational research network spanning Australia and New Zealand (The D3 Group; www.thed3group.org), we firstly depict MH as a silent public health problem that is generally more concerning than the three classical D3s. Second, we argue that diverse research inputs are needed to undertake a multi-faceted attack on this problem, and outline demarcated opacities as the central research target. Third, we suggest that, given past victories studying other dental conditions, enamel researchers stand to make crucial contributions to the understanding and prevention of MH. Finally, to focus geographically diverse research interests onto this nascent field, further internationalisation of The D3 Group is warranted

EXERCISE-INDUCED ELEVATIONS IN SKELETAL MUSCLE HISTAMINE CONTRIBUTES TO INCREASED POST-EXERCISE CAPILLARY PERMEABILITY

C.K. Edwards, M.R. Ely, D.C. Sieck, J.E. Mangum, E.A. Larson, J.R. Halliwill FACSM. University of Oregon. Eugene, OR Histamine, an endogenously released molecule in immune and inflammatory responses increases local vasodilation, blood flow, and capillary permeability. During exercise, histamine is produced within exercising muscle and contributes to an elevated post-exercise blood flow. The histamine-induced post-exercise vasodilation is contained within previously exercised muscle as histamine concentrations are not elevated in non-exercised muscle (i.e. arms during leg exercise). It is unknown if intramuscular histamine also contributes to elevate capillary permeability following exercise. PURPOSE: To compare capillary permeability of the leg before and after prolonged unilateral knee-extension exercise under normal conditions and when histaminergic signaling is blocked. It was hypothesized that H1/H2receptor antihistamines would decrease capillary permeability following exercise in an exercised leg but not in a resting leg. METHODS: Six (2F) volunteers performed 60 min of unilateral knee-extension exercise at 60% of peak power after consuming either Placebo or histamine (H1/H2) receptor antagonists (Blockade). A capillary filtration coefficient (CFC) reflecting the rate of change in limb girth per rise in venous pressure was calculated using venous occlusion plethysmography. A CFC was calculated prior to (PRE) and following (POST) exercise in both the exercised leg (EL) and the resting leg (RL). Data were analyzed with a 3-way RM ANOVA and presented as Means±SEM. RESULTS: On average, CFC increased 161±90% (PRE: 2.5±1.0 to POST: 6.6±2.3 μg·100g-1·min-1·mmHg-1) in the EL and 38±31% (PRE: 4.8 to POST: 6.5 μg·100g-1·min-1·mmHg-1) in the RL during Placebo. Blockade attenuated the exercise-induced rise in CFC in the EL to 13±41% (PRE = 4.3±1.3 to POST = 4.9±1.8 μg·100g-1·min-1·mmHg-1) and in the RL 2±45% (PRE: 3.8±1.4 to POST: 3.8±1.7 μg·100g-1·min-1·mmHg-1). Due to the high variability in the measures there was a trend for CFC to increase with exercise (P=0.161), for Blockade to attenuate the rise in CFC (P=0.363), and for a leg by drug interaction (P=0.289). CONCLUSION: These initial data suggest that exercise-induced histamine production contributes to the elevated CFC within exercised limbs. Support provided by: ACSM NW Student Research Award; O’Day Fellowship; Carol Carver Pay-it-Forward Thesis Gran

HISTAMINE RECEPTOR-MEDIATED SUSTAINED POST-EXERCISE VASODILATION IN YOUNG TRAINED AND UNTRAINED ADULTS

M.J. Luttrell, P.M. Abdala, M.R. Ely, D.C. Sieck, J.E. Mangum, J.R. Halliwill FACSM University of Oregon, Eugene, OR Histamine-mediated sustained post-exercise vasodilation in response to one hour of dynamic knee extension has been established in young, recreationally active adults. It is unknown whether endurance exercise training modifies this response in young adults. PURPOSE: The purpose of this study was to test the hypothesis that sedentary young adults have similar histamine receptor mediated sustained post-exercise vasodilator responses compared to endurance trained young adults. METHODS: A randomized, double-blind placebo-controlled crossover study including 6 endurance trained (3F, 3M; ages 18-26) and 5 sedentary (3F, 2M; ages 22-29) adults was completed. Subjects consumed either combined histamine H1 and H2 receptor blockade with 540 mg fexofenadine (Allegra, H1 receptor blocker) and 300mg ranitidine (Zantac, H2 receptor blocker), or placebo pills containing only the inactive ingredients of fexofenadine and ranitidine. Pre-exercise vascular blood flow and conductance measurements were made every 30 minutes for 90 minutes. Post-exercise measurements were made every 30 minutes for 2 hours. Subjects completed 1 hour of dynamic knee extension exercise at 60% of maximal work rate. Subject demographics and baseline variables were analyzed using independent t-tests. Post-exercise differences between groups in the blockade and placebo conditions were analyzed using a mixed model ANOVA with repeated measures. All values are reported as mean ± SE. RESULTS: The endurance trained group had higher self-reported weekly physical activity compared to the sedentary group (73.03 ± 10.5 vs. 27.4 ± 9.5 METhr/wk, p=0.012). Pre-exercise mean arterial pressure was not different between the two groups in either placebo or blockade conditions (trained placebo: 83±2, trained blockade: 84±2, sedentary placebo: 84±1, sedentary blockade: 86±3 mmHg, p=0.745). Baseline femoral vascular conductance was not different between groups in either placebo or blockade condition (p=0.905). At 60 minutes post exercise, the change in femoral vascular conductance from baseline was not different between the groups for either placebo or blockade condition, although there was a trend towards drug effect of histamine receptor blockade (p=0.192). CONCLUSION: These preliminary results suggest that there is no difference in post-exercise femoral vascular conductance between endurance trained and sedentary young adults. Supported by NIH grant HL115027