Granulocyte-targeted therapies for airway diseases

The average respiration rate for an adult is 12-20 breaths per minute, which constantly exposes the lungs to allergens and harmful particles. As a result, respiratory diseases, which includes asthma, chronic obstructive pulmonary disease (COPD) and acute lower respiratory tract infections (LTRI), are a major cause of death worldwide. Although asthma, COPD and LTRI are distinctly different diseases with separate mechanisms of disease progression, they do share a common feature – airway inflammation with intense recruitment and activation of granulocytes and mast cells. Neutrophils, eosinophils, basophils, and mast cells are crucial players in host defense against pathogens and maintenance of lung homeostasis. Upon contact with harmful particles, part of the pulmonary defense mechanism is to recruit these cells into the airways. Despite their protective nature, overactivation or accumulation of granulocytes and mast cells in the lungs results in unwanted chronic airway inflammation and damage. As such, understanding the bright and the dark side of these leukocytes in lung physiology paves the way for the development of therapies targeting this important mechanism of disease. Here we discuss the role of granulocytes in respiratory diseases and summarize therapeutic strategies focused on granulocyte recruitment and activation in the lungs

Extracellular Ca2+ transients affect poly-(R)-3-hydroxybutyrate regulation by the AtoS-AtoC system in Escherichia coli

Journal URL: http://www.biochemj.org/bj/default.htmEscherichia coli is exposed to wide extracellular concentrations of Ca2+, whereas the cytosolic levels of the ion are subject to stringent control and are implicated in many physiological functions. The present study shows that extracellularCa2+ controls cPHB [complexed poly-(R)-3-hydroxybutyrate] biosynthesis through the AtoS-AtoC two-component system. Maximal cPHB accumulation was observed at higher [Ca2+]e (extracellular Ca2+ concentration) in AtoS-AtoC-expressing E. coli compared with their _atoSC counterparts, in both cytosolic and membrane fractions. The reversal of EGTA-mediated down-regulation of cPHB biosynthesis by the addition of Ca2+ and Mg2+ was under the control of the AtoS-AtoC system.Moreover, the Ca2+-channel blocker verapamil reduced total and membrane-bound cPHB levels, the inhibitory effect being circumvented by Ca2+ addition only in atoSC+ bacteria. Histamine and compound 48/80 affected cPHB accumulation in a [Ca2+]e-dependent manner directed by theAtoS-AtoC system. In conclusion, these data provide evidence for the involvement of external Ca2+ on cPHB synthesis regulated by the AtoS-AtoC two-component system, thus linking Ca2+ with a signal transduction system, most probably through a transporter. Key words: AtoS-AtoC two-component system, atoDAEB, calcium, calcium channel blocker, histamine, poly-(R)-3- hydroxybutyrate

Histamine in two component system-mediated bacterial signaling

Histamine is a key mediator governing vital cellular processes in mammals beyond its decisive role in inflammation. Recent evidence implies additional actions in both eukaryotes and prokaryotes. Besides its function in host defense against bacterial infections, histamine elicits largely undefined actions in microorganisms that may contribute to bacteria-host interactions. Bacterial proliferation and adaptation are governed by sophisticated signal transduction networks, including the versatile two-component systems (TCSs) that comprise sensor histidine kinases and response regulators and rely on phosphotransfer mechanisms to exert their modulatory function. The AtoSC TCS regulates fundamental cellular processes such as short-chain fatty acid metabolism, poly-(R)-3-hydroxybutyrate (cPHB) biosynthesis and chemotaxis in Escherichia coli. The implication of exogenous histamine in the AtoSC-mediated cPHB biosynthesis and in E. coli chemotactic behavior is indicative of a putative function of histamine in bacterial physiology. The data raise questions on the significance of histamine actions in bacteria-host symbiosis, dysbiosis and pathogenicity as well as on the possible consequences upon therapeutic administration of histamine receptor-targeting agents and in particular ligands of the recently identified immunomodulatory H-4 receptor

Histamine Pharmacology and New CNS Drug Targets

During the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H3 and H4 receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H3 receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimers, or Parkinson’s disease, while the first H3 receptor ligands have already entered phase IIII clinical trials. Interestingly, the localization of the immunomodulatory H4 receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current translational research approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration

Histamine Involvement in Visual Development and Adaptation

PURPOSE. This study evaluated the level of histamine in the interaction between the environment and the visual system during lifespan development, exploring potential sex differences. METHODS. Male and female Wistar rats, reared in standard laboratory or enriched-environment cages from birth to prepuberty or adulthood, were sacrificed during the critical period for visual development at postnatal day (P) 25 (P25) or in adulthood at P90. Additionally, animals born in standard conditions were exposed to an enriched environment at P90 and sacrificed at P150. The optic chiasm and the visual cortex were dissected out and tissue histamine was quantified fluorophotometrically. Statistical analyses were performed by ANOVA. RESULTS. Histamine levels in the optic chiasm were higher in male than in female rats at all ages. Comparable sex differences in the visual cortex were observed only during prepuberty. Basal histamine content in the optic chiasm was higher in prepuberty and decreased in adulthood in a sex-independent manner. Exposure to an enriched environment decreased optic chiasm histamine levels in both sexes and resulted in no sex difference in the cortical histamine levels at any age. Increased amine levels were detected in the optic chiasm of female rats exposed to an enriched environment during adulthood. CONCLUSIONS. This study presents first evidence associating central histamine levels with the visual system development and environmental adaptation, thus providing the lead for the investigation of the hitherto elusive role of histamine in the regulation of visual processes. Furthermore, the findings challenge the impact of laboratory animal raising environments in developmental and behavioral studies. (Invest Ophthalmol Vis Sci. 2012; 53: 7498-7503) DOI:10.1167/iovs.12-1080

DERMANYSSUS GALLINAE and its public Health consequences

The poultry red mite (PRM), Dermanyssus gallinae, is best known as a threat to the laying hen industry, adversely affecting hen health and welfare through both its feeding behavior and role as disease vector. However, due to its genetic plasticity, PRM attacks wild and synanthropic birds as well and, more importantly, has consequences in non-avian hosts, particularly humans. Poultry workers, farmers, technicians and veterinarians are most at risk for dermanyssosis and the inclusion of PRM as an occupational hazard has been recommended. In the mean time, reports of dermatological complaints have increased in frequency, in several countries, including residential town settings (private homes, hospitals, public offices), typically linked to nearby feral (pigeons, sparrows, etc.) (mostly recently-abandoned) birds’ nests. Attacks of D. gallinae to humans cause pruritus, skin lesions characterized by small erythematous papules -mostly concentrated on arms, hands, chest, legs - which are often misdiagnosed by medical clinicians. The medical significance of dermanyssosis is exacerbated by the potential of the PRM to carry and transmit zoonotic diseases of both bacterial and viral origin. Additionally, in the poultry farm context, since chemicals are still the dominant means of PRM control, they may have adverse effects on humans, both directly, for workers exposed to chemicals and indirectly through consumption of poultry meat and eggs containing pesticide residues. The recent scandal on the use of an unlicensed product (fipronil) provides clear evidence of such risk. The CoReMi COST Action also focuses on the One Health paradigm, aimed to encourage interactions and exchange information among medical practitioners, environmentalists, veterinarians, academics, industrial researchers, and promoting actions for an increase awareness of D. gallinae infestations in humans, mite identification, development of diagnostic tools, advance and use of non-chemicals control measures, in order to limit the consequences of D. gallinae and safeguard animal, human and environmental health. The authors wish to thank the European Cooperation in Science and Technology (COST Action (FA1404 - COREMI)“Improving current understanding and research for sustainable control of the poultry red mite Dermanyssus gallinae”)

Mast cells contribute to the resolution of allergic inflammation by releasing resolvin D1

Background: Mast cells are initiators and main effectors of allergic inflammation, together with eosinophils, with whom they can interact in a physical and soluble cross-talk with marked pro-inflammatory features, the Allergic Effector Unit. The pro-resolution role of mast cells, alone or in co-culture with eosinophils, has not been characterized yet. Objectives: We aimed to investigate select pro-resolution pathways in mast cells in vitro and in vivo in allergic inflammation. Methods: In vitro, we employed human and murine mast cells and analyzed release of resolvin D1 and expression of 15-lipoxygenase after IgE-mediated activation. We performed co-culture of IgE-activated mast cells with peripheral blood eosinophils and investigated 15-lipoxygenase expression and Resolvin D1 release. In vivo, we performed Ovalbumin/Alum and Ovalbumin/S. aureus enterotoxin B allergic peritonitis model in Wild Type mice following a MC “overshoot” protocol. Results: We found that IgE-activated mast cells release significant amounts of resolvin D1 30 min after activation, while 15-lipoxygenase expression remained unchanged. Resolvin D1 release was found to be decreased in IgE-activated mast cells co-cultured with peripheral blood eosinophils for 30 min In vivo, mast cell-overshoot mice exhibited a trend of reduced inflammation, together with increased peritoneal resolvin D1 release. Conclusions: Mast cells can actively contribute to resolution of allergic inflammation by releasing resolvin D1