Eosinophil-Epithelial Cell Interactions in Asthma.

BACKGROUND: Eosinophils have numerous roles in type 2 inflammation depending on their activation states in the blood and airway or after encounter with inflammatory mediators. Airway epithelial cells have a sentinel role in the lung and, by instructing eosinophils, likely have a foundational role in asthma pathogenesis. SUMMARY: In this review, we discuss various topics related to eosinophil-epithelial cell interactions in asthma, including the influence of eosinophils and eosinophil products, e.g., granule proteins, on epithelial cell function, expression, secretion, and plasticity; the effects of epithelial released factors, including oxylipins, cytokines, and other mediators on eosinophils, e.g., on their activation, expression, and survival; possible mechanisms of eosinophil-epithelial cell adhesion; and the role of intra-epithelial eosinophils in asthma. KEY MESSAGES: We suggest that eosinophils and their products can have both injurious and beneficial effects on airway epithelial cells in asthma and that there are bidirectional interactions and signaling between eosinophils and airway epithelial cells in asthma.

P2X7 signaling influences the production of pro-resolving and pro-inflammatory lipid mediators in alveolar macrophages derived from individuals with asthma.

Few new therapeutics exist to target airway inflammation in mild-to-moderate asthma. Alveolar macrophages regulate airway inflammation by producing proresolving eicosanoids. We hypothesized that stimulation of the purinergic receptor P2X7 in macrophages from individuals with asthma produces eicosanoids associated with airway inflammation and resolution, and that these responses are predicted, in part, by P2X7 pore function. Study subjects were recruited in an Institutional Review Board (IRB)-approved study. Alveolar macrophages were recovered from bronchoalveolar lavage fluid following bronchoscopy. Purinergic receptor classification was performed using flow cytometry and fluorescent cell assay. Macrophages were stimulated in vitro and eicosanoids were measured via ELISA or enzyme immunoassay (EIA) in the presence and absence of P2X7-specific agonist [2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate tri(triethylammonium) salt (Bz-ATP)] and antagonist (AZD9056). Functional P2X7 pore status was confirmed in a live cell assay using P2X7-specific agonists and antagonists. Alveolar macrophages produced increased quantities of the oxylipins lipoxin A4 (LXA4), resolvin D1 (RvD1), and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) following stimulation with Bz-ATP compared with vehicle controls, responses that were attenuated in the presence of the P2X7-selective antagonist, AZD9056. LXA4 and RvD1 production was greatest at 1 h, whereas 15(S)-HETE was maximally produced 24 h. Prostaglandin E-2 and resolvin E1 were minimally produced by P2X7 activation, indicating differential signaling pathways involved in eicosanoid production in alveolar macrophages derived from individuals with asthma. The early production of the proresolving eicosanoids, LXA4 and resolvin D1, is regulated by P2X7, whereas generation of the proinflammatory eicosanoid, 15(S)-HETE, is only partially regulated through P2X7 signaling and reaches maximal production after the peak in proresolving eicosanoids.NEW & NOTEWORTHY Alveolar macrophages obtained from individuals with asthma produce soluble lipid mediators in response to P2X7 purinergic receptor signaling. Proinflammatory mediators may contribute to asthma exacerbations but proresolving mediators may help with resolution of asthma loss of control. These specialized proresolving lipid mediators may serve as future potential therapeutics for asthma exacerbation resolution and recovery.

Role of transient receptor potential vanilloid 1 in the modulation of airway smooth muscle tone and calcium handling.

Asthma is a common disorder characterized, in part, by airway smooth muscle (ASM) hyperresponsiveness. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel expressed on airway nerve fibers that modulates afferent signals, resulting in cough, and potentially bronchoconstriction. In the present study, the TRPV1 transcript was detected by RT-PCR in primary cultured human ASM cells, and the TRPV1 protein was detected in ASM of human trachea by immunohistochemistry. Proximity ligation assays suggest that TRPV1 is expressed in the sarcoplasmic reticulum membrane of human ASM cells in close association with sarco/endoplasmic reticulum Ca2+-ATPase-2. In guinea pig tracheal ring organ bath experiments, the TRPV1 agonist capsaicin led to ASM contraction, but this contraction was significantly attenuated by the sodium channel inhibitor bupivacaine (n = 4, P < 0.05) and the neurokinin-2 receptor antagonist GR-159897 (n = 4, P < 0.05), suggesting that this contraction is neutrally mediated. However, pretreatment of guinea pig and human ASM in organ bath experiments with the TRPV1 antagonist capsazepine inhibited the maintenance phase of an acetylcholine-induced contraction (n = 4, P < 0.01 for both species). Similarly, capsazepine inhibited methacholine-induced contraction of peripheral airways in mouse precision-cut lung slice (PCLS) experiments (n = 4-5, P < 0.05). Although capsazepine did not inhibit store-operated calcium entry in mouse ASM cells in PCLS (n = 4-7, P = nonsignificant), it did inhibit calcium oscillations (n = 3, P < 0.001). These studies suggest that TRPV1 is expressed on ASM, including the SR, but that ASM TRPV1 activation does not play a significant role in initiation of ASM contraction. However, capsazepine does inhibit maintenance of contraction, likely by inhibiting calcium oscillations.

Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cß.

Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond ß-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo (n = 4 and n = 5, respectively, P < 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo (n = 6-8, P < 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine (n = 6, P < 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) (n = 7, P < 0.05; n = 7, P < 0.05, respectively), and PLCß enzymes (n = 6, P < 0.001 and n = 6, P < 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium (n = 11, P < 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation (n = 9, P < 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCß and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction.

Active components of ginger potentiate ß-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins.

ß-Agonists are the first-line therapy to alleviate asthma symptoms by acutely relaxing the airway. Purified components of ginger relax airway smooth muscle (ASM), but the mechanisms are unclear. By elucidating these mechanisms, we can explore the use of phytotherapeutics in combination with traditional asthma therapies. The objectives of this study were to: (1) determine if 6-gingerol, 8-gingerol, or 6-shogaol potentiate ß-agonist-induced ASM relaxation; and (2) define the mechanism(s) of action responsible for this potentiation. Human ASM was contracted in organ baths. Tissues were relaxed dose dependently with ß-agonist, isoproterenol, in the presence of vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 µM). Primary human ASM cells were used for cellular experiments. Purified phosphodiesterase (PDE) 4D or phospholipase C ß enzyme was used to assess inhibitory activity of ginger components using fluorescent assays. A G-LISA assay was used to determine the effects of ginger constituents on Ras homolog gene family member A activation. Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-Shogaol showed the largest shift in isoproterenol half-maximal effective concentration. 6-Gingerol, 8-gingerol, or 6-shogaol significantly inhibited PDE4D, whereas 8-gingerol and 6-shogaol also inhibited phospholipase C ß activity. 6-Shogaol alone inhibited Ras homolog gene family member A activation. In human ASM cells, these constituents decreased phosphorylation of 17-kD protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase and 8-gingerol decreased myosin light chain phosphorylation. Isolated components of ginger potentiate ß-agonist-induced relaxation in human ASM. This potentiation involves PDE4D inhibition and cytoskeletal regulatory proteins. Together with ß-agonists, 6-gingerol, 8-gingerol, or 6-shogaol may augment existing asthma therapy, resulting in relief of symptoms through complementary intracellular pathways.

Social occupational therapy: conversations about a Brazilian experience.

BACKGROUND: Researchers and practitioners worldwide have advocated for the development of critical perspectives in occupational therapy to examine the structural influences of social exclusion and injustice experienced by individuals, groups, and communities. To take action against social exclusion and injustice, Brazilian occupational therapists have been developing "social occupational therapy," referring to practice that is focused on social issues and funded outside the health system. PURPOSE: This paper presents a Brazilian perspective on the concept and practice of social occupational therapy. Illustrations are drawn from 12 studies, developed between 2008 and 2013, which were completed with socially vulnerable youth through an ongoing university-community engagement partnership in São Carlos, São Paulo State, Brazil. KEY ISSUES: The authors discuss possibilities and challenges for developing a socially committed, transformative occupational therapy outside the health system. IMPLICATIONS: Occupational therapists may wish to seize opportunities to address social issues and attract funding beyond health services.

Effects of ginger and its constituents on airway smooth muscle relaxation and calcium regulation.

The prevalence of asthma has increased in recent years, and is characterized by airway hyperresponsiveness and inflammation. Many patients report using alternative therapies to self-treat asthma symptoms as adjuncts to short-acting and long-acting ß-agonists and inhaled corticosteroids (ICS). As many as 40% of patients with asthma use herbal therapies to manage asthma symptoms, often without proven efficacy or known mechanisms of action. Therefore, investigations of both the therapeutic and possible detrimental effects of isolated components of herbal treatments on the airway are important. We hypothesized that ginger and its active components induce bronchodilation by modulating intracellular calcium ([Ca(2+)](i)) in airway smooth muscle (ASM). In isolated human ASM, ginger caused significant and rapid relaxation. Four purified constituents of ginger were subsequently tested for ASM relaxant properties in both guinea pig and human tracheas: [6]-gingerol, [8]-gingerol, and [6]-shogaol induced rapid relaxation of precontracted ASM (100-300 µM), whereas [10]-gingerol failed to induce relaxation. In human ASM cells, exposure to [6]-gingerol, [8]-gingerol, and [6]-shogaol, but not [10]-gingerol (100 µM), blunted subsequent Ca(2+) responses to bradykinin (10 µM) and S-(-)-Bay K 8644 (10 µM). In A/J mice, the nebulization of [8]-gingerol (100 µM), 15 minutes before methacholine challenge, significantly attenuated airway resistance, compared with vehicle. Taken together, these novel data show that ginger and its isolated active components, [6]-gingerol, [8]-gingerol, and [6]-shogaol, relax ASM, and [8]-gingerol attenuates airway hyperresponsiveness, in part by altering [Ca(2+)](i) regulation. These purified compounds may provide a therapeutic option alone or in combination with accepted therapeutics, including ß(2)-agonists, in airway diseases such as asthma.

Quercetin acutely relaxes airway smooth muscle and potentiates ß-agonist-induced relaxation via dual phosphodiesterase inhibition of PLCß and PDE4.

Asthma is a disease of the airways with symptoms including exaggerated airway narrowing and airway inflammation. Early asthma therapies used methylxanthines to relieve symptoms, in part, by inhibiting cyclic nucleotide phosphodiesterases (PDEs), the enzyme responsible for degrading cAMP. The classification of tissue-specific PDE subtypes and the clinical introduction of PDE-selective inhibitors for chronic obstructive pulmonary disease (i.e., roflumilast) have reopened the possibility of using PDE inhibition in the treatment of asthma. Quercetin is a naturally derived PDE4-selective inhibitor found in fruits, vegetables, and tea. We hypothesized that quercetin relaxes airway smooth muscle via cAMP-mediated pathways and augments ß-agonist relaxation. Tracheal rings from male A/J mice were mounted in myographs and contracted with acetylcholine (ACh). Addition of quercetin (100 nM-1 mM) acutely and concentration-dependently relaxed airway rings precontracted with ACh. In separate studies, pretreatment with quercetin (100 µM) prevented force generation upon exposure to ACh. In additional studies, quercetin (50 µM) significantly potentiated isoproterenol-induced relaxations. In in vitro assays, quercetin directly attenuated phospholipase C activity, decreased inositol phosphate synthesis, and decreased intracellular calcium responses to Gq-coupled agonists (histamine or bradykinin). Finally, nebulization of quercetin (100 µM) in an in vivo model of airway responsiveness significantly attenuated methacholine-induced increases in airway resistance. These novel data show that the natural PDE4-selective inhibitor quercetin may provide therapeutic relief of asthma symptoms and decrease reliance on short-acting ß-agonists.

Development and Dynamic Responsiveness of the Acute Asthma Exacerbation Survey in Patients With Moderate to Severe Disease.

BACKGROUND: The recall periods and response scales of existing surveys of asthma control are poorly suited for studying acute exacerbations. OBJECTIVE: To develop an instrument able to predict exacerbations after the onset of acute symptoms and with a recall window sufficiently short to study recovery. METHODS: We developed the six-item Acute Asthma Exacerbation Survey (AAES). Data were collected at baseline, acute, and recovery visits within an established longitudinal protocol for participants with severe asthma. Participants scheduled acute study visits at the first sign of a cold. Nasal lavage samples and lung function measurements were also collected. The AAES data were analyzed using Cronbach α, Spearman correlations, and Kruskal-Wallace methods. We used logistic regression for predictors of bursts of oral corticosteroids (OCS). RESULTS: Of 130 participants studied at baseline, 52 returned for an acute visit. The AAES scores were elevated at the acute visit and returned to baseline after recovery independently of respiratory virus detection. Cronbach α for the AAES was 0.853, 0.822, and 0.889 at the three respective visits. Compared with participants not needing burst OCS, those with exacerbations had higher acute AAES scores (16 [13.5-18] vs 11.5 [8.2-14], median [interquartile range]; P = .017) and a larger reduction from baseline in lung function. For each 3-point increase in AAES scores, the odds ratio for burst OCS use was 1.64 (95% CI, 1.04-2.57; P = .030). CONCLUSIONS: The AAES is internally consistent and dynamically responsive during acute asthma exacerbations. Additional validation studies are warranted to support future trials and aid in clinical decision-making.

Estrogen effects on human airway smooth muscle involve cAMP and protein kinase A.

Clinically observed differences in airway reactivity and asthma exacerbations in women at different life stages suggest a role for sex steroids in modulating airway function although their targets and mechanisms of action are still being explored. We have previously shown that clinically relevant concentrations of exogenous estrogen acutely decrease intracellular calcium ([Ca(2+)](i)) in human airway smooth muscle (ASM), thereby facilitating bronchodilation. In this study, we hypothesized that estrogens modulate cyclic nucleotide regulation, resulting in decreased [Ca(2+)](i) in human ASM. In Fura-2-loaded human ASM cells, 1 nM 17ß-estradiol (E(2)) potentiated the inhibitory effect of the ß-adrenoceptor (ß-AR) agonist isoproterenol (ISO; 100 nM) on histamine-mediated Ca(2+) entry. Inhibition of protein kinase A (PKA) activity (KT5720; 100 nM) attenuated E(2) effects on [Ca(2+)](i). Acute treatment with E(2) increased cAMP levels in ASM cells comparable to that of ISO (100 pM). In acetylcholine-contracted airways from female guinea pigs or female humans, E(2) potentiated ISO-induced relaxation. These novel data suggest that, in human ASM, physiologically relevant concentrations of estrogens act via estrogen receptors (ERs) and the cAMP pathway to nongenomically reduce [Ca(2+)](i), thus promoting bronchodilation. Activation of ERs may be a novel adjunct therapeutic avenue in reactive airway diseases in combination with established cAMP-activating therapies such as ß(2)-agonists.

Orthotopic Liver Transplantation in a Patient with Acutely Decompensated Liver Disease and Personal History of Malignant Hyperthermia.

Introduction: Orthotopic liver transplants are characterized by sudden changes in hemodynamics, intraoperative hemorrhage, metabolic and electrolyte derangements, and arrhythmias. Many of these features are also hallmarks of malignant hyperthermia episodes and make differentiation difficult intraoperatively. Additionally, the treatment for malignant hyperthermia, dantrolene, can cause hepatotoxicity in already damaged native livers and newly reperfused organ allografts. Thus, it is imperative to avoid a triggering anesthetic in these patients. Here we report on a successful total intravenous anesthetic in a malignant hyperthermia susceptible individual undergoing an orthotopic liver transplant for acutely decompensated end-stage liver disease. Case Presentation. A 49-year-old male with a past medical history significant for malignant hyperthermia episodes as a child was admitted with decompensated alcoholic cirrhosis. He underwent uneventful total intravenous general anesthesia with propofol and sufentanil continuous infusions for an orthotopic liver transplant. He required minimal vasoactive agents to maintain a mean arterial blood pressure >65 mmHg and was extubated on postoperative day 1. Conclusions: Total intravenous anesthesia is necessary for patients with a personal history of malignant hyperthermia. However, this type of general anesthesia is difficult in the setting of fluctuating hemodynamics, hemorrhage, and changes in drug metabolism and clearance during the anhepatic and reperfusion phases of an orthotopic liver transplant. Propofol and sufentanil continuous infusions provided stable hemodynamics and an excellent plane of anesthesia throughout the case and should be considered in other individuals undergoing this procedure who require a total intravenous anesthetic.

Estrogen increases nitric-oxide production in human bronchial epithelium.

Although sex differences in asthma severity are recognized, the mechanisms by which sex steroids such as estrogen influence the airway are still under investigation. Airway tone, a key aspect of asthma, represents a balance between bronchoconstriction and dilation. Nitric oxide (NO) from the bronchial epithelium is an endogenous bronchodilator. We hypothesized that estrogens facilitate bronchodilation by generating NO in bronchial epithelium. In acutely dissociated human bronchial epithelial cells from female patients exposure to 17ß-estradiol (E(2); 10 pM-100 nM) resulted in rapid increase of diaminofluorescein fluorescence (NO indicator) within minutes, comparable with that induced by ATP (20 µM). Estrogen receptor (ER) isoform-specific agonists (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC) (ERα) and diaryl-propionitrile (DPN) (ERß) stimulated NO production to comparable levels and at comparable rates, whereas the ER antagonist 7α,17ß-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780) (1 µM) was inhibitory. Estrogen effects on NO were mediated via caveolin-1 (blocked using the caveolin-1 scaffolding domain peptide) and by increased intracellular calcium concentration [prevented by 20 µM 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester but not by blocking Ca(2+) influx using LaCl(3)]. Estrogen increased endothelial NO synthase activation (inhibited by 100 µM N(G)-nitro-l-arginine methyl ester) and phosphorylated Akt. In epithelium-intact human bronchial rings contracted with acetylcholine (1 µM), E(2), THC, and DPN all produced acute bronchodilation in a dose-dependent fashion. Such bronchodilatory effects were substantially reduced by epithelial denudation. Overall, these data indicate that estrogens, acting via ERα or ERß, can acutely produce NO in airway epithelium (akin to vascular endothelium). Estrogen-induced NO and its impairment may contribute to altered bronchodilation in women with asthma.

Introducing the Leadership in Enabling Occupation (LEO) model.

BACKGROUND: Occupational therapy is a broad profession yet access to services remains restricted and uneven across Canada. Access to the potential breadth of occupational therapy is severely restrained by complex supply, retention, and funding challenges. To improve access to occupational therapy, widespread leadership is needed by all practitioners. PURPOSE: This brief report introduces the Leadership in Enabling Occupation (LEO) Model, which displays the inter-relationship of four elements of everyday leadership as described in "Positioning Occupational Therapy for Leadership," Section IV, of Enabling Occupation II: Advancing a Vision of Health, Well-being and Justice through Occupation (Townsend & Polatajko, 2007). KEY ISSUES: All occupational therapists have the power to develop leadership capacity within and beyond designated leadership positions. IMPLICATIONS: LEO is a leadership tool to extend all occupational therapists' strategic use of scholarship, new accountability approaches, existing and new funding, and workforce planning to improve access to occupational therapy.

Rapid effects of estrogen on intracellular Ca2+ regulation in human airway smooth muscle.

The severity of asthma, a disease characterized by airway hyperresponsiveness and inflammation, is enhanced in some women during the menstrual cycle and during pregnancy but relieved in others. These clinical findings suggest that sex steroids modulate airway tone. Based on well-known relaxant effects of estrogens on vascular smooth muscle, we hypothesized that estrogens relax airway smooth muscle (ASM), thus facilitating bronchodilation. In ASM tissues from female patients, Western and immunocytochemical analyses confirmed the presence of both estrogen receptor (ER) isoforms, ERalpha and ERbeta. In fura 2-loaded, dissociated ASM cells maintained in culture, acute exposure to physiological concentrations of 17beta-estradiol (E(2); 100 pM to 10 nM) decreased the intracellular Ca(2+) ([Ca(2+)](i)) response to 1 muM histamine, an effect reversed by the ER antagonist ICI-182,780. The ERalpha-selective agonist (R,R)-THC had a greater reducing effect on [Ca(2+)](i) responses to histamine and 1 muM ACh compared with the ERbeta-selective agonist (DPN). The effects of E(2) on [Ca(2+)](i) were mediated, at least in part, via decreased Ca(2+) influx through l-type channels and store-operated Ca(2+) entry but not via Ca(2+)-activated K(+) channels, receptor-operated entry, or sarcoplasmic reticulum reuptake. Overall, these data support our hypothesis that estrogens relax ASM and suggest a potentially novel therapeutic target in airway hyperresponsiveness.

Do occupational justice concepts inform occupational therapists' practice? A scoping review.

BACKGROUND.: Occupational justice and related concepts can inform practices directed at injustice and the lack of rights in daily life. Brazilian ideas about social occupational therapy seem to be similar to these concepts about inequality. PURPOSE.: This study aimed to answer the questions, "Do occupational justice concepts inform occupational therapists' professional actions?" and "How are occupational justice concepts connected to Brazilian ideas about social occupational therapy?" METHOD.: A secondary analysis was undertaken of a scoping review using occupational justice and related concepts as keywords. Descriptive and categorical analyses were used to classify the extract data. FINDINGS.: We selected 42 articles that specify occupational therapy practices, classified as individual approaches (n = 13), individual-integrated-with-social approaches (n = 22), and social approaches (n = 7). It was found that occupational justice concepts have informed individual approaches and that the second and third approaches can be connected with social occupational therapy. IMPLICATIONS.: Dialogue for sharing knowledge, concepts, and practices of occupational therapy worldwide can be inspired by this review.

Development of a 500-Hz masking-level difference protocol for clinic use.

The purpose of this series of experiments was to develop a simple, 500-Hz masking-level difference (MLD) protocol that could be implemented easily in the clinic to assess auditory perceptual abilities using an audio compact disc. Five, 300-ms tones with 250-ms intertone intervals were embedded in 3-s bursts of 200-800 Hz noise presented at 42.2-dB pressure-spectrum level with 4-5 s interstimulus intervals. The homophasic and antiphasic conditions were interleaved with the signal-to-noise ratios decreasing in 2-dB steps. A single-interval, "yes/no" response task was used. Three experiments were performed on 24-28 listeners with normal hearing. The mean SoNo thresholds (58.1- to 59.5-dB SPL) and the mean SpiNo thresholds (45.1- to 46.0-dB SPL) produced approximately 13-dB MLDs. Experiment 3 included a SoNpi condition that had a mean threshold of 48.8-dB SPL and a 10.0-dB MLD. The mean test, retest of the SoNo and SpiNo thresholds on 15 listeners was < 0.5 dB. Over the three experiments, 95% of the listeners had SpiNo MLDs that were > or = 10 dB.

Sex differences and sex steroids in lung health and disease.

Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span.

Can we find better bronchodilators to relieve asthma symptoms?

Bronchodilators are the first line therapy during acute asthmatic exacerbations to reverse airway obstruction primarily by relaxing airway smooth muscle. Only three categories of bronchodilators exist in clinical practice: ß-adrenergic agonists, anticholinergics, and methylxanthines. Each of these categories have specific drugs dating back to the early 20th century, raising the question of whether or not we can find better bronchodilators. While caffeine, theophylline, atropine, and epinephrine were the first generations of therapeutics in each of these drug classes, there is no question that improvements have been made in the bronchodilators in each of these classes. In the following editorial, we will briefly describe new classes of potential bronchodilators including: novel PDE inhibitors, natural phytotherapeutics, bitter taste receptor ligands, and chloride channel modulators, which have the potential to be used alone or in combination with existing bronchodilators to reverse acute airway obstruction in the future.