RESUMO
The crises of climate change and biodiversity loss are interlinked and must be addressed jointly. A proposed solution for reducing reliance on fossil fuels, and thus mitigating climate change, is the transition from conventional combustion-engine to electric vehicles. This transition currently requires additional mineral resources, such as nickel and cobalt used in car batteries, presently obtained from land-based mines. Most options to meet this demand are associated with some biodiversity loss. One proposal is to mine the deep seabed, a vast, relatively pristine and mostly unexplored region of our planet. Few comparisons of environmental impacts of solely expanding land-based mining versus extending mining to the deep seabed for the additional resources exist and for biodiversity only qualitative. Here, we present a framework that facilitates a holistic comparison of relative ecosystem impacts by mining, using empirical data from relevant environmental metrics. This framework (Environmental Impact Wheel) includes a suite of physicochemical and biological components, rather than a few selected metrics, surrogates, or proxies. It is modified from the "recovery wheel" presented in the International Standards for the Practice of Ecological Restoration to address impacts rather than recovery. The wheel includes six attributes (physical condition, community composition, structural diversity, ecosystem function, external exchanges and absence of threats). Each has 3-5 sub attributes, in turn measured with several indicators. The framework includes five steps: (1) identifying geographic scope; (2) identifying relevant spatiotemporal scales; (3) selecting relevant indicators for each sub-attribute; (4) aggregating changes in indicators to scores; and (5) generating Environmental Impact Wheels for targeted comparisons. To move forward comparisons of land-based with deep seabed mining, thresholds of the indicators that reflect the range in severity of environmental impacts are needed. Indicators should be based on clearly articulated environmental goals, with objectives and targets that are specific, measurable, achievable, relevant, and time bound.
Assuntos
Mineração , Biodiversidade , Ecossistema , Meio Ambiente , Conservação dos Recursos Naturais , Mudança ClimáticaRESUMO
Paraliparis hawaiiensis n.sp. is described from the north-western Hawaiian Islands from two specimens collected at 2196 and 3055 m. It differs from other North Pacific Ocean species in its chin pore arrangement, tooth pattern and body proportions. Although liparid specimens have previously been collected from Hawaii, they were undescribed and are now lost. Therefore, this is the first liparid species described from the archipelago. In situ photographs of Hawaiian snailfishes are also shown and discussed here.
Assuntos
Perciformes/anatomia & histologia , Perciformes/classificação , Animais , HavaíRESUMO
Airway hyperresponsiveness is a key characteristic of human asthma and a marker for asthma-like conditions in animals. F1 mice derived from A/J and C57BL/6J display a phenotype which resembles the asthma-like phenotype of the A/J mice. Since airway responsiveness failed to segregate as a mendelian trait, we show significant linkage at two loci, Bhr1 (lod = 3.0) and Bhr2 (lod = 3.7) on chromosomes 2 and 15. A third locus, Bhr3 (lod = 2.83), maps to chromosome 17. Each of these loci maps near candidate loci implicated in the pathobiology of asthma. Our study represents the first linkages established through a genome-wide survey of airway hyperresponsiveness in any mammal.
Assuntos
Asma/genética , Asma/fisiopatologia , Mapeamento Cromossômico , Pulmão/fisiologia , Testes de Função Respiratória , Análise de Variância , Animais , Cruzamentos Genéticos , DNA/análise , DNA/isolamento & purificação , Feminino , Ligação Genética , Genótipo , Humanos , Rim/metabolismo , Escore Lod , Pulmão/efeitos dos fármacos , Masculino , Mamíferos , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Parassimpatomiméticos/farmacologia , Fenótipo , Pletismografia , Reação em Cadeia da PolimeraseRESUMO
Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.
Assuntos
Antiasmáticos/uso terapêutico , Araquidonato 5-Lipoxigenase/genética , Asma/tratamento farmacológico , Asma/genética , Hidroxiureia/análogos & derivados , Regiões Promotoras Genéticas , Alelos , Asma/enzimologia , Frequência do Gene , Variação Genética , Humanos , Hidroxiureia/uso terapêutico , Inibidores de Lipoxigenase/uso terapêutico , Fenótipo , Resultado do TratamentoRESUMO
Owing to the paucity of data on the red muscle of deep-sea fishes, the goal of this study was to determine the proportions of red muscle in demersal fishes and its enzymatic activities to characterize how routine swimming abilities change with depths of occurrence. Cross sectional analysis of the trunk musculature was used to evaluate the proportion of red muscle in 38 species of Californian demersal fishes living at depths between 100 and 3000 m. The activity of metabolic enzymes was also assayed in a sub-set of 18 species. Benthic fishes had lower proportions of red muscle and lower metabolic enzyme activities than benthopelagic species. Mean proportion of red muscle declined significantly with depth with the greatest range of values in shallow waters and species with low proportions found at all depths. This suggested that while sedentary species occur at all depths, the most active species occur in shallow waters. Citrate synthase activity declined significantly with depth across all species, indicating that the mass-specific metabolic capacity of red muscle is lower in deep-sea species. These patterns may be explained by coupling of red and white muscle physiologies, a decrease in physical energy of the environment with depth or by the prevalence of anguilliform body forms and swimming modes in deep-living species.
Assuntos
Peixes/fisiologia , Músculos/enzimologia , Natação/fisiologia , Animais , California , Citrato (si)-Sintase/metabolismo , Meio Ambiente , Oceano PacíficoRESUMO
BACKGROUND: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. METHODS: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. FINDINGS: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. INTERPRETATION: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. FUNDING: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".
Assuntos
Síndrome de Down , Células-Tronco Pluripotentes Induzidas , Adulto , Humanos , Envelhecimento , Diferenciação Celular , Síndrome de Down/genética , Quinases DyrkRESUMO
Increased suspended sediment concentrations (SSC) are a major stressor across aquatic habitats. Here, the literature was synthesized to show that animal responses to increases in relative SSC (test concentration/natural background concentration) were similar in type and negative across different shallow-water (marine, estuarine, freshwater) habitats. Further, animal sensitivities are similar across habitats based on relative SSC and occur starting at low relative SSC increases in all habitats despite differences in natural background SSC. Based upon these similarities in relative SSC sensitivities, deep-sea sensitivity values for acute exposure to increased SSC, where empirical data are almost non-existent, were estimated. Because of the low natural SSC in deep sea environments, very small increases in absolute SSC could result in acute effects. How the methods and results can be used to inform regulatory thresholds are discussed. Because of the large variability in shallow water datasets and differences between deep-sea and shallow-water habitats, deep-sea specific data are needed to verify the estimates and improve their precision. Following the precautionary principle and the results presented here, it is recommended that the threshold for acute plume impacts is set very close to natural background levels.
Assuntos
Monitoramento Ambiental , Água , Animais , Monitoramento Ambiental/métodos , Mineração , EcossistemaRESUMO
Airway hyperresponsiveness (AHR) is a hallmark of asthma and a heritable polygenic trait in the mouse. In the mouse, candidate gene products of hematopoietic origin implicated in asthma mapped to the regions of the previously defined quantitative trait loci. Since hematopoietic cells have been implicated in the pathogenesis of asthma, we evaluated the role of hematopoietic cells in general and T cells specifically in the genetic modulation of native airway responsiveness in mice. Here, with the use of bone marrow transplantation, anti-T-cell monoclonal antibody treatment and T-cell transfer, we demonstrate that intrinsic non-atopic AHR is mediated by T lymphocytes. Our data support the novel concept that, in the absence of identified environmental influences, T cells enhance genetically determined airway responsiveness.
Assuntos
Asma/genética , Asma/imunologia , Sistema Respiratório/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Asma/etiologia , Transplante de Medula Óssea , Broncoconstritores/farmacologia , Relação Dose-Resposta a Droga , Depleção Linfocítica , Masculino , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Especificidade da Espécie , TimectomiaRESUMO
Eotaxin is a member of the C-C family of chemokines and is related during antigen challenge in a guinea pig model of allergic airway inflammation (asthma). Consistent with its putative role in eosinophilic inflammation, eotaxin induces the selective infiltration of eosinophils when injected into the lung and skin. Using a guinea pig lung cDNA library, we have cloned full-length eotaxin cDNA. The cDNA encodes a protein of 96 amino acids, including a putative 23-amino acid hydrophobic leader sequence, followed by 73 amino acids composing the mature active eotaxin protein. The protein-coding region of this cDNA is 73, 71, 50, and 48% identical in nucleic acid sequence to those of human macrophage chemoattractant protein (MCP) 3, MCP-1, macrophage inflammatory protein (MIP) 1 alpha, and RANTES, respectively. Analysis of genomic DNA suggested that there is a single eotaxin gene in guinea pig which is apparently conserved in mice. High constitutive levels of eotaxin mRNA expression were observed in the lung, while the intestines, stomach, spleen, liver, heart, thymus, testes, and kidney expressed lower levels. To determine if eotaxin mRNA levels are elevated during allergen-induced eosinophilic airway inflammation, ovalbumin (OVA)-sensitized guinea pigs were challenged with aerosolized antigen. Compared with the lungs from saline-challenged animals, eotaxin mRNA levels increased sixfold within 3 h and returned to baseline by 6 h. Thus, eotaxin mRNA levels are increased in response to allergen challenge during the late phase response. The identification of constitutive eotaxin mRNA expression in multiple tissues suggests that in addition to regulating airway eosinophilia, eotaxin is likely to be involved in eosinophil recruitment into other tissues as well as in baseline tissue homing.
Assuntos
Alérgenos/imunologia , Quimiocinas CC , Citocinas/genética , Pulmão/metabolismo , RNA Mensageiro/análise , Sequência de Aminoácidos , Animais , Sequência de Bases , Quimiocina CCL11 , DNA Complementar/análise , Cobaias , Humanos , Hipersensibilidade/metabolismo , Masculino , Dados de Sequência MolecularRESUMO
Leukotriene B (LTB), a potent lipid chemotactic factor for neutrophils, is 5S,12R-dihydroxy-6,14-cis,8,10-trans-eicosatetraenoic acid (Fig 1), based upon direct comparison of natural LTB with synthetic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-di-HETE) stereoisomers in three biological assays. Of the six synthetic stereoisomers evaluated, only the 5S,12R,6,14-cis,8,10-trans compound had chemotactic potency for human neutrophils in vitro that was comparable to that of natural LTB, with a concentration of 3 X 10(9-9) M eliciting a one-half maximum response. In contrast, the racemic mixture of 5R,12R- and 5S,12S-6,10-trans,8,14-cis, the racemic mixture of 5S,12R- and 5R,12S-6,10-trans,8,14-cis, the 5S,12R-6,8-trans,10,14-cis, the 5S,12R-6,8,10-trans,14-cis, and the 5S,12S-6,8,10-trans,14-cis stereoisomers required concentrations of 3 X 10(-7) to 1 X 10(-6) M to elicit comparable responses. Only natural LTB and its synthetic counterpart elicited a local neutrophil infiltration when injected into the skin of the rhesus monkey at 10 ng and 100 ng per site. Natural and synthetic LTB at a concentration of 3 X 10(-8) M each provoked an EC25 contractile response of guinea pig pulmonary parenchymal strips in vitro, whereas the other four tested stereoisomers of 5,12-di-HETE were inactive at this concentration. Structure-function analyses suggest that the neutrophil chemotactic activity depends critically upon the C-1 to C-12 domain, including the stereochemistry of the 6-,8-,and 10-olefinic bonds and the presence of both hydroxyl groups.
Assuntos
Ácidos Araquidônicos , Animais , Fenômenos Químicos , Química , Quimiotaxia de Leucócito , Cobaias , Humanos , Leucotrieno B4 , Macaca mulatta , Músculo Liso , Neutrófilos , Testes Cutâneos , Espasmo/induzido quimicamente , EstereoisomerismoRESUMO
Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mice was significantly less than that observed in similarly treated NOS2 and WT groups. These findings demonstrate an important function for the nNOS isoform in controlling the inducibility of airway hyperresponsiveness in this model of allergic asthma.
Assuntos
Asma/imunologia , Óxido Nítrico Sintase/deficiência , Pneumonia/imunologia , Animais , Asma/enzimologia , Asma/etiologia , Líquido da Lavagem Broncoalveolar/citologia , Cálcio/metabolismo , Modelos Animais de Doenças , Marcação de Genes/métodos , Histocitoquímica , Humanos , Isoenzimas/deficiência , Pulmão/enzimologia , Cloreto de Metacolina , Camundongos , Camundongos Knockout , Ovalbumina , PletismografiaRESUMO
The 2008-2013 World Health Organization (WHO) action plan on noncommunicable diseases (NCDs) includes chronic respiratory diseases as one of its four priorities. Major chronic respiratory diseases (CRDs) include asthma and rhinitis, chronic obstructive pulmonary disease, occupational lung diseases, sleep-disordered breathing, pulmonary hypertension, bronchiectiasis and pulmonary interstitial diseases. A billion people suffer from chronic respiratory diseases, the majority being in developing countries. CRDs have major adverse effects on the life and disability of patients. Effective intervention plans can prevent and control CRDs, thus reducing morbidity and mortality. A prioritised research agenda should encapsulate all of these considerations in the frame of the global fight against NCDs. This requires both CRD-targeted interventions and transverse NCD programmes which include CRDs, with emphasis on health promotion and disease prevention.
Assuntos
Saúde Global , Pneumopatias/prevenção & controle , Pneumopatias/terapia , Pesquisa/tendências , Organização Mundial da Saúde , Doença Crônica , Comorbidade , Humanos , Pneumopatias/epidemiologia , PrevalênciaRESUMO
Obstruction of airways by viscous sputum causes lung damage in patients with cystic fibrosis (CF). Sputum samples from CF patients were shown to contain filamentous actin. Human plasma gelsolin, a protein that severs actin filaments, rapidly decreased the viscosity of CF sputum samples in vitro. Gc globulin and deoxyribonuclease I, proteins that sequester monomeric actin but do not sever actin filaments, were less efficient than gelsolin in diminishing sputum viscosity. These results suggest that gelsolin may have therapeutic potential as a mucolytic agent in CF patients.
Assuntos
Actinas/análise , Fibrose Cística/metabolismo , Gelsolina/farmacologia , Escarro/efeitos dos fármacos , Actinas/química , Adulto , Desoxirribonuclease I/metabolismo , Humanos , Técnicas In Vitro , Escarro/química , Viscosidade , Proteína de Ligação a Vitamina D/farmacologiaRESUMO
Maximum expiratory flow rate at 30 percent of vital capacity above residual volume served as an index of airway obstruction in comparing the effects of leukotriene C and histamine administered by aerosol to five normal persons. Leukotriene C was 600 to 9500 times more potent than histamine on a molar basis in producing an equivalent decrement in the residual volume. The leukotriene C response was slow in onset and prolonged, reminiscent of the effects of aerosol allergen challenge in asthmatic allergic subjects.
Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Brônquios/efeitos dos fármacos , SRS-A/farmacologia , Adulto , Relação Dose-Resposta a Droga , Feminino , Histamina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Prostaglandinas F/farmacologia , Fatores de TempoRESUMO
Asthma is a serious health problem throughout the world. During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it effectively. However, recommendations for asthma care need to be adapted to local conditions, resources and services. Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations. A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines. The 2006 report contains important new themes. First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions. The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised.
Assuntos
Asma/diagnóstico , Asma/prevenção & controle , Asma/terapia , Corticosteroides/farmacologia , Antiasmáticos/uso terapêutico , Asma/epidemiologia , Diagnóstico Diferencial , Gerenciamento Clínico , Saúde Global , Guias como Assunto , Humanos , Comunicação Interdisciplinar , Saúde Pública , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Pneumologia/métodos , Fatores de RiscoRESUMO
The effects of intravenous administration of a purified preparation of slow-reacting substance of anaphylaxis (SRS-A), histamine, bradykinin, and prostaglandin F(2alpha) (PGF(2alpha)) on the mechanics of respiration were assessed in the unanesthetized guinea pig. Geometrically increasing doses of SRS-A resulted in graded decreases in average pulmonary compliance, with only modest increases in average pulmonary resistance. A dose with apparent maximal effects. 3,000 U/kg, resulted in a decrease of 49+/-7% of compliance below control values, with an increase in resistance of 24+/-8% above control. Intravenous administration of geometrically increasing amounts of histamine, bradykinin, and prostaglandin F(2alpha) also resulted in decreased compliance; but in each case this was accompanied by a marked increase in respiratory resistance. A decrease of compliance of approximately 50%, induced by intravenous histamine, bradykinin, or PGF(2alpha), was accompanied by an increase of 60-140% in resistance. Thus, intravenously administered SRS-A alters pulmonary mechanics with a more peripheral effect than any of the other agents tested.
Assuntos
Bradicinina/administração & dosagem , Histamina/administração & dosagem , Pulmão/efeitos dos fármacos , Prostaglandinas/administração & dosagem , SRS-A/administração & dosagem , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Histamina/farmacologia , Infusões Parenterais , Complacência Pulmonar/efeitos dos fármacos , Masculino , Prostaglandinas/farmacologia , Respiração/efeitos dos fármacos , SRS-A/farmacologia , Fatores de TempoRESUMO
The responses of isolated guinea pig tracheal spirals and parenchymal strips to histamine and carbachol were compared. The parenchymal strip, a 1.5 x 1.5 x 20-mm strip cut from the periphery of the lung, constricted at a lower dose and had a larger maximal response to histamine than to carbachol. In contrast, the response of the tracheal spiral to equimolar doses of histamine or carbachol was the same. The responsiveness of both muscle strips to histamine was decreased by treatment with the H1 receptor antagonist mepyramine (0.1 micrometer), and the response to carbachol was blocked by treatment with atropine (0.1 micrometer). Indomethacin (3 micrometer), cimetidine (1 micrometer), propranolol (10 micrometer), and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (4 micrometer) did not alter the differential response of the two strips to histamine and carbachol. The differential response of parenchymal strips with many, few, or no conducting airways and blood vessels was identical, suggesting that the contractile element is alveolar duct smooth muscle or alveolar contractile elements. This differential pharmacologic response in vitro is consistent with the in vivo observation that histamine causes more peripheral airway constriction than does acetylcholine.
Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Carbacol/farmacologia , Histamina/farmacologia , Acetilcolina/farmacologia , Animais , Interações Medicamentosas , Cobaias , Técnicas In Vitro , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Traqueia/irrigação sanguínea , Traqueia/efeitos dos fármacosRESUMO
The effects of enzyme inhibitors on vasoactive intestinal peptide (VIP)-induced decreases in airway opening pressure (PaO) and VIP-like immunoreactivity (VIP-LI) recovery were studied in isolated tracheal superfused guinea pig lungs. In the absence of inhibitors, VIP 0.38 (95% CI 0.33-0.54) nmol/kg animal, resulted in a 50% decrease in PaO and 33% of a 1 nmol/kg VIP dose was recovered as intact VIP. In the presence of two combinations of enzyme inhibitors, SCH 32615 (S, 10 microM) and aprotinin (A, 500 tyrpsin inhibitor units [TIU]/kg) or S and soybean trypsin inhibitor (T, 500 TIU/kg), VIP caused a significantly greater decrease in PaO and greater quantities of VIP were recovered from lung effluent (both P < 0.001). The addition of captopril, (3 microM), leupeptin (4 microM), or bestatin (1 microM) failed to further increase pulmonary relaxation or recovery of VIP-LI. When given singly, A, T, and S did not augment the effects or recovery of VIP. The efficacy of S (a specific inhibitor of neutral endopeptidase [NEP]) and A and T (serine protease inhibitors) thus implicated NEP and at least one serine protease as primary modulators of VIP activity in the guinea pig lung. We sought to corroborate this finding by characterizing the predominant amino acid sites at which VIP is hydrolized in the lung. When [mono(125I)iodo-Tyr10]VIP was offered to the lung, in the presence and absence of the active inhibitors, cleavage products consistent with activity by NEP and a tryptic enzyme were recovered. These data demonstrate that NEP and a peptidase with an inhibitor profile and cleavage pattern compatible with a tryptic enzyme inactivate VIP in a physiologically competitive manner.
Assuntos
Endopeptidases/metabolismo , Pulmão/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Inibidores de Proteases/farmacologia , Traqueia/fisiologia , Peptídeo Intestinal Vasoativo/farmacologia , Animais , Aprotinina/farmacologia , Captopril/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Leucina/análogos & derivados , Leucina/farmacologia , Leupeptinas/farmacologia , Pulmão/efeitos dos fármacos , Masculino , Músculo Liso/efeitos dos fármacos , Perfusão , Fatores de Tempo , Traqueia/efeitos dos fármacos , Inibidores da Tripsina/farmacologiaRESUMO
We used genetically mast cell-deficient WBB6F1-W/Wv and WCB6F1-S1/S1d mice and the congenic normal (+/+) mice to investigate the effects of intravenous infusion of goat antimouse IgE on heart rate (HR), pulmonary dynamic compliance (Cdyn), pulmonary conductance (GL), and survival. In WBB6F1-+/+ and WCB6F1-+/+ mice, anti-IgE induced extensive degranulation of tracheobronchial mast cells, as well as significant elevation of HR, significant reductions in Cdyn and GL and, in some cases, death. In contrast, W/Wv and S1/S1d mice exhibited little or no pathophysiological responses and no mortality after challenge with anti-IgE. In W/Wv mice reconstituted with mast cells by intravenous administration of bone marrow cells derived from congenic +/+ mice (+/+ BM----W/Wv mice), anti-IgE induced extensive mast cell degranulation, as well as pathophysiological responses and mortality similar to those observed in WBB6F1-+/+ mice. These findings suggest a critical role for mast cells in the development of the cardiopulmonary changes and mortality associated with anti-IgE-induced anaphylaxis.