Asthma
Diseases

Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis. 2013

Sera of asthma patients were characterized by increased levels of methionine, glutamine, and histidine and by decreased levels of formate, methanol, acetate, choline, O-phosphocholine, arginine, and glucose.

BITTER TASTE RECEPTORS ON AIRWAY SMOOTH MUSCLE INDUCE BRONCHODILATION.

Airway obstructive diseases (asthma and chronic obstructive pulmonary disease [COPD]) currently affect more than 300 million people worldwide. Dysfunction of airway smooth muscle (ASM) cells, a major cell type in the respiratory tree, plays a pivotal role in promoting progression of these diseases and in contributing to their symptoms. With their ability to contract and relax, these cells regulate the diameter and length of conducting airways, controlling dead space and resistance to airflow to and from gas-exchanging areas. Their excessive contraction, as seen in patients with asthma and COPD, can fully close the airways, thereby hindering gas exchange and threatening life. Not surprisingly, bronchodilators have been used as the medication of choice for asthmatic attacks and as a standard therapy for managing COPD. However, available bronchodilators have adverse side effects, and are not sufficiently effective for severe asthmatics and many other COPD patients.

Therapies for COPD and asthma both include antagonists directed to bronchoconstrictive receptors, and agonists directed to receptors that relax airway smooth muscle (ASM). The major receptor signaling family of ASM that regulates contraction and relaxation are G-protein-coupled receptors.

BITTER TASTE RECEPTORS.

Bitter tastants represent a new class of compounds with potential role as potent bronchodilators. Recent experimental evidences (Deshpande et al.) found that cultured ASM cells express G-protein-coupled bitter taste receptors (TAS2Rs), a class of proteins long thought to be expressed only in the specialized epithelial cells in the taste buds of the tongue that allows organisms to avoid harmful toxins and noxious substances characterized by bitterness. TAS2Rs on human airway smooth muscle (ASM) were considered to be avoidance receptors for inhalants, leading to ASM contraction and bronchospasm. TAS2R agonists such as saccharin , chloroquine and denatonium evoked increased ASM [Ca²⁺]i in a Gβγ, PLCβ and IP3-receptor dependent manner which would be expected (like acetylcholine) to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM, and dilation of airways that was 3-fold greater than β2 adrenergic agonists, the most commonly used bronchodilators to treat asthma and COPD.
These GPCRs consist of at least 25 receptor subtypes, each recognizing a repertoire of agonists that usually overlaps with other bitter taste receptors, creating a redundant, broadly-tuned, avoidance and rejection network.
These receptors are also found in the anterior nasal cavity where they promote sneezing and regulate respiratory rate, again repulsion-like responses to noxious stimuli.
A recent report has also identified bitter taste receptors on motile cilia of airway epithelial cells that increase beat frequency, considered a mechanical defense against noxious inhalants.

FIRST HYPOTHESIS OF BITTER TASTANT-INDUCED BRONCHODILATION.

The finding of bitter taste receptors on ASM led to an original hypothesis that certain bronchospastic disorders, such as occupational asthma, might be caused by environmental inhalants acting at these airway receptors leading to contraction and bronchoconstriction. This notion was based on the fact that bitter taste receptors couple to increases in [Ca ²⁺]i in specialized taste cells of the tongue, and this signal is also found with known bronchoconstrictive GPCRs such as those for histamine, acetylcholine and bradykinin in ASM cells.

The pro-bronchoconstrictive GPCRs couple to Gαq, increase [Ca ²⁺]i, and trigger ASM contraction. In contrast, GPCRs coupled to Gαs increase cAMP, relax ASM and bronchodilate, with the β2-adrenergic receptor being the target for β-agonists, the most commonly utilized therapeutic for bronchospasm. Given that bitter signaling has been thought to serve an aversion response, it was assumed that ASM bitter taste receptors would act to contract the muscle leading to bronchoconstriction, with shortness of breath as the cue to escape from a noxious environment. Bitter tastants signaled to increased [Ca ²⁺]i in ASM via a Gβγ, PLCβ and IP3 receptor manner. The increased [Ca ²⁺]i would be expected to cause ASM constriction, such as that observed with Gαq-coupled receptor activation, but marked relaxation in intact airways of humans as well as isolated human ASM cells was observed instead.

This first hypothesis argued that bitter tastants generate localized Ca ²⁺ signals that open cell surface Ca ²⁺ channels resulting in membrane hyperpolarization, leading to relaxation. Contraction of ASM cells by bronchoconstrictors decreased thanks to this mechanism.

Bitter taste receptors on airway smooth muscle bronchodilate by a localized calcium flux and reverse obstruction.2011

RECENT HYPOTHESIS OF BITTER TASTANT-INDUCED BRONCHODILATION.

A new study revealed two major differences in Ca ²⁺ signaling compared to the previous hypothesis. First, the authors of the first study reported that bitter tastant increased [Ca ²⁺]i to a level comparable to bronchoconstrictors (such as histamine, acetylcholine and bradykinin). In freshly isolated ASM, bitter tastants only modestly increase [Ca ²⁺]i to a level much lower than that produced by bronchoconstrictors. Second, it was proposed that bitter tastants generate local Ca ²⁺ events. However, in freshly isolated ASM, bitter tastants do not increase local Ca ²⁺ releases such as Ca ²⁺ puffs and Ca ²⁺ sparks. A reason for these two discrepancies may be that the first studies were conducted in cultured ASM cell lines; compared to freshly isolated ASM, these cells display a different phenotype by altering the expression of receptors, ion channels, and contractile proteins. The aforementioned two differences and another difference in which bitter tastants do not activate large-conductance Ca ²⁺-activated K ⁺ channels strongly argue that bitter tastant-induced bronchodilation is highly unlikely to result from the generation of local Ca ²⁺ events, which in turn activate large-conductance Ca ²⁺-activated K ⁺ channel and hyperpolarize the membrane as proposed.

According to new studies the effects of tastants are different according to the contraction state of ASM cells.

1. Ca ²⁺ changes in cells at rest are mediated via activation of the canonical bitter taste signaling cascade (i.e., TAS2R-gustducin-phospholipase Cβ [PLCβ]- inositol 1,4,5-triphosphate receptor [IP3R]), and are not sufficient to impact airway contractility.
2. In the presence of bronchoconstrictors, bitter tastants lowered [Ca ²⁺]i while at the same time relaxing the precontracted cells, and this response was reversible. This reversion is based on the fact that bitter tastants are able to inhibit L-type voltage-dependent Ca ²⁺ channels (VDCCs), resulting in reversal in [Ca ²⁺]i.

What remains unknown is whether the subunit βγ of G protein associated to bitter tastant receptors directly or indirectly inhibits these channels, and the structural basis for this inhibition. Given that Gβγ can directly inhibit K ⁺ channels and N-type Ca ²⁺ in several cell types, it is likely that Gβγ acts on L-type VDCCs in a similar manner.

The Cellular and Molecular Basis of Bitter Tastant-Induced Bronchodilation.2013

FUTURE THERAPIES

Although bitter tastants are promising candidates to be developed as a new class of bronchodilators, and the findings in recent studies provide the cellular and molecular rationale for this line of inquiry, chloroquine and denatonium (main bitter tastants) may not be ideal candidates because of the high concentration needed to fully relax precontracted ASM. This caveat, however, should not dampen enthusiasm for this endeavor as there are many thousands of bitter tastants available from plants and animals, and numerous bitter small molecules synthesized by research laboratories and a variety of companies over the years. In fact, bitter tastants can stimulate bitter taste receptors at concentrations in the nanomolar range such as strychnine and aristolochic acid. Therefore, it is highly likely that bitter tastants with a highly potent bronchodilating action can be discovered. Searching for these bitter tastants is of clinical significance because the current bronchodilators are insufficient for treating severe asthma and many COPD patients.

How bitter medicine could clear up asthma.2013

CAN OTHER TASTE RECEPTORS HAVE A ROLE ON BROCHODILATION?

The receptor mechanisms that drive taste also are utilized by numerous systems throughout the body. How and why these so-called taste receptors are used to regulate digestion and respiration is now a matter of intense study.

Taste isn't just for taste buds anymore.2011

“Taste” in the airways

The first description of taste-related signaling components in the airway was a report by Zancanaro and colleagues describing the presence of gustducin-expressing cells in the vomeronasal organ, which is a specialized part of the olfactory system found in many vertebrates but absent in adult humans. The gustducin-expressing cells in the vomeronasal organ are scattered epithelial cells mainly distributed along the incoming ducts of the organ and within the non-sensory epithelium of the organ itself. The morphology of these cells is similar to chemosensory and they are usually referred as solitary chemosensory cells (SCCs). The function of the receptors in many tissues remains unclear despite recent advances.

Until now (2013) there are not studies which state the expression of sweet, sour, umami and salty receptors on the airway smooth muscle of bronchi. So we don’t know if tastants other than bitter one have bronchodilation effects.

ESTROGEN AND ASTHMA

ROLE OF FEMALE SEX HORMONES, ESTRADIOL AND PROGESTERONE, IN MAST CELL BEHAVIOR.

ABSTRACT.
Female sex hormones have long been suspected to have an effect on mast cell (MC) behavior. This assumption is based on the expression of hormone receptors in MCs as well as on the fact that many MC-related pathophysiological alterations have a different prevalence in females than in males. Further, serum IgE levels are much higher in allergic female mice compared to male mice. Ovariectomized rats developed less airway inflammation compared to sham controls. Following estrogen replacement ovariectomized rats re-established airway inflammation levels' found in intact females. In humans, a much higher asthma prevalence was found in women at reproductive age as compared to men. Serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma. Around 30-40% of women who have asthma experienced worsening of their symptoms during the perimenstrual phase, the so-called perimenstrual asthma. Postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma. Beside, estrus cycle dependent changes on female sex hormones are related to changes on MC number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine MC maturation and degranulation. We will discuss here the currently available information concerning the role of these female sex hormones on MC behavior.

Role of female sex hormones, estradiol and progesterone, in mast cell behavior, 2001

INTRODUCTION.
Mast cells (MCs) belong to the innate-compartment of the immune system and are widely known for their role in allergic reactions via their binding to IgE receptor. MCs are a common cellular component of both connective and mucosal tissues. Beside this, MCs contain a wide range of biologically active molecules, including biogenic amines, heparin or heparan sulfate proteoglycans, neutral proteases, and neuropeptides. In addition, upon stimulation, they also produce and eject a large number of factors. Taking these characteristics together, it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes.

In addition to the very well known and described mechanism of MC activation and posterior degranulation throughout IgE receptor, several other alternative but not redundant mechanisms of MC activation have been described. Among others, female sex hormones, estradiol and progesterone, have been proposed to activate MC. We will discuss in this review about the effect of female sex hormones on MC functionality.

Adapters in the organization of mast cell signaling, 2009

MAST CELLS EXPRESS ESTRADIOL AND PROGESTERONE RECEPTORS AND FURTHER RESPOND TO THESE HORMONES.

Female sex steroid hormones act primarily via their receptors: estrogen via estrogen receptor ERα or ERβ, progesterone via progesterone receptor PR-A or PR-B. Steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression. However, in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane, whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes. In this regard, it has been shown that classical ERα at the membrane but not in the nucleus mediates 17β-estradiol (E2)-induced rapid signaling to kinase activation. Similarly, extra-nuclear PR induces activation of ERK/MAPK kinases, which lead to cell surviving as well as cells migration. We and other authors have demonstrated the expression of, estradiol and progesterone receptors in human, mouse, and rat MCs have shown mRNA expression of ERα but not ERβ in human and mouse MCs.

Alongside the authors have also shown that E2 rapidly stimulated MC degranulation which could be blocked by tamoxifen , a tissue specific ER antagonist, clearly indicating that estradiol-induced MC degranulation throughout one of its receptors. Bone marrow-derived MCs (BMMCs) isolated from ERα knockout animals did not degranulate in response to E2 treatment confirming that the E2 effect on MCs is more likely mediated by the ERα. Due to the rapid onset of E2 effect on MC activation the authors concluded that E2 in this context does not function through the classical (genomic) mechanisms, which require enhanced mRNA and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane-associated (non-genomic) form of ER. We were additionally able to show that the human mast cell line (HMC-1) treated in vitro with physiological concentration of E2 and P4 significantly increased the synthesis of β-tryptase, which is a serine proteinase abundantly produced by MCs, and is a marker of MC maturation. Beside, E2 and P4 treatment induced degranulation of HMC-1 in vitro.

Minireview: extranuclear steroid receptors: roles in modulation of cell functions, 2011":http://www.ncbi.nlm.nih.gov/pubmed/20861220

Supporting the idea of female sex hormones having an effect on MC function, have demonstrated that allergen skin prick tests (SPT), a very sensitive and specific tests to detect allergic sensitization in atopic patients, is altered in women upon hormonal changes during the menstrual cycle.
In addition to female sex hormone receptor expression, MCs have been also shown to express androgen receptor. However, testosterone treatment had no effect on MC degranulation.

Human mast cells express androgen receptors but treatment with testosterone exerts no influence on IgE-independent mast cell degranulation elicited by neuromuscular blocking agents, 2010

INFLUENCE OF ESTRADIOL AND PROGESTERONE ON MC FUNCTION: DO THESE HORMONES PLAY A ROLE IN MC-RELATED DISEASE?

The idea that female sex hormones, E2 and P4, may affect MC functionality and therefore have an influence on the symptoms of MC-associated disorders has long been suggested. Asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years. A number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences. Beside this, postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma. Furthermore, 30–40% of women who had asthma, experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle (*perimenstrual asthma*) being the time point when E2 and P4 concentrations are changing rapidly. In this context, it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years, particularly in developing countries. This may be related to the increase of low concentrations of environmental like-estrogen compounds. These estrogen-like compounds, called xenoestrogens, are present in the environmental pollutants mainly in water and food. They are able not only to activate MCs but enhance MC degranulation upon allergen cross-linking of IgE which may explain the above described increment of allergic diseases in the last years in developing countries.

In an animal model of allergic disease, the role of female sex hormone was tested. Female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice. Levels of IgE are much higher in allergic female mice compared to their syngeneic male. Female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals. However, estrogen replacement in the ovariectomized animals re-established airway inflammation levels of intact females. Treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease. Thus, the direct effect of these hormones on disease development is hereby demonstrated.

Beyond the well-documented effects of estradiol and progesterone on MC function in MC-associated diseases, these hormones were further implicated in controlling different MC process under physiological conditions. For instance, estradiol was showed to be a potent inducer of ovarian MC degranulation, which seems to be a necessary factor during the process of oocyte ovulation.

Environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators, 2007

Perimenstrual asthma: a syndrome without known cause or cure, 2003

MC NUMBER, MATURATION, AND DEGRANULATION IN THE UTERUS ARE UNDER THE CONTROL OF FEMALE SEX HORMONES.

The presence of MCs in the uterus has been already described in many species including human, mouse, rat, hamster as well as goat. Besides, the number of MCs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on MC recruitment to the uterus. Ovariectomized mice, in which estradiol and progesterone are almost absent, have less number of uterine MCs compared to control, non-ovariectomized animals. Hormonal replacement, estradiol alone or in combination with progesterone, restored the number of uterine MCs after ovariectomization, which was comparable to the levels observed in control mice. Hormonal replacement additionally induced an augmentation in the levels of MC-related proteases expression in the uterus as well as boosted MC degranulation. This is of particular importance because upon degranulation, MCs release several molecules (histamine, proteases, metalloproteinases, pro-angiogenic factors), all very well known to account for the process of embryo implantation.

Mast cells in the normal uterus and in dysfunctional uterine bleeding, 1991

CONCLUSION.

Mast cells, the so-called unicellular glands, once solely known as effectors cells of the innate immune system only activated by IgE cross-linking to the IgE receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones, estradiol and progesterone. Strong data in the last years reinforced the idea that these hormones are crucial component of MC behavior not only in physiological conditions but also in several MC pathological situations. Deciphering the mechanisms by which female sex hormones activate MCs and under which conditions these happens, alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells.

Notizie dall'Italia

Linee Guida 2010

Asma: utili interventi miglioramento qualitativo
I cosiddetti interventi QI migliorano gli esiti ed i procedimenti assistenziali ambulatoriali per l'asma infantile. Nonostante la disponibilità di linee guida pratiche per la gestione dell'asma pediatrico, rimane un significativo divario fra le terapie ottimali e quelle realmente applicate in questo campo: ad esempio, è stato dimostrato che molti bambini asmatici non fanno uso di medicinali preventivi, e ne' loro ne' i loro tutori sanno in molti casi come prevenire o trattare un attacco asmatico. Vista la loro apparente efficacia, una meticolosa descrizione degli interventi QI ne avanzerebbe le applicazioni nell'asma peditrico. L'obiettivo chiave per gli studi futuri in materia consisterà l'identificazione delle strategie che possano ridurre con efficacia le visite d'urgenza ed in pronto soccorso, ridurre i costi complessivi ed incrementare la qualità della vita. (Arch Pediatr Adolesc Med. 2009; 163: 572-81)

Respirazione notturna, asma e turbe comportamento
I disordini della respirazione nel sonno sono associati a problemi comportamentali nei bambini asmatici. Sono stati effettuati studi che hanno posto in correlazione i sintomi asmatici sia con i problemi comportamentali infantili che con i disturbi del sonno, e vi sono prove limitate, ma in aumento, che i bambini con disordini della respirazione nel sonno possano mostrare un comportamento peggiore. Sono necessarie ulteriori indagini per determinare se il trattamento dei disordini del sonno possa aiutare a diminuire i problemi comportamentali in questa popolazione, ma nel frattempo è necessario che i medici curanti ricerchino la presenza dei disordini respiratori nel sonno in tutti i bambini asmatici, e considerino la loro presenza come un possibile fattore di rischio di problemi comportamentali. (Pediatrics 2009; 124: 218-25)

SNLG - Sistema Nazionale Linee Guida
Asma Bronchiale (Linea Guida Regione Toscana)
Con il Termine di Asma Bronchiale (AB) si Intende un'Ostruzione
Reversibile delle Vie Aeree che Riconosce come Substrato
Anatomo Patologico una Flogosi delle Vie Respiratorie del Tutto
Peculiare e piu' o Meno Marcata, che e' Responsabile dei Sintomi
e dell'Iperreattivita' Bronchiale a Stimoli Anche Minimi. Anche se
Queste Caratteristiche Consentono una Definizione Clinica
Precisa dell' Asma Bronchiale, Tuttavia la Divera Eta' Insorgenza
i diversi Fattori di Rischio che Condizionano la Patogenese, la
Cronicita' della Flogosi che nel Tempo Causa Fenomeni di
Rimodellamento delle Vie Respiratorie con Perdita Progressiva
delle Reversibilita' dell'Ostruzione, e l'Associazione a Seconda
dell' Eta' con Altre Malattie Respiratorie o Sistemiche,
Individuano Quadro Clinici a Volte assai Diversi in cui si Richiede
una Stretta Integrazione tra le Diverse Competenze
Specialistiche. Tale Integrazione si Rende Necessaria Non Solo
per una Corretta Diagnosi Eziologia e Clinica e per un Corretto
Trattamento, ma per la Prevenzione delle Forme Complicate
e piu' Critiche e per una Valida Riabilitazione
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