RESUMEN
BACKGROUND: Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO2 (silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory. METHODS: Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO2/kg in mice. Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-ß (Aß) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests. RESULTS: Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aß peptide, and memory impairment in mice. CONCLUSION: The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.
Asunto(s)
Neumonía , Silicosis , Animales , Ratones , Dióxido de Silicio/toxicidad , Ratones Endogámicos C57BL , Silicosis/patología , Neumonía/inducido químicamente , Neumonía/patología , Inflamación/inducido químicamente , Inflamación/patología , Pulmón/patología , Sinapsis/patología , Péptidos beta-Amiloides , Hipocampo/patología , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/patología , CitocinasRESUMEN
Recently, several studies have reported that respiratory disease may be associated with an increased production of free radicals. In this context, 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) is a free radical-generating compound widely used to mimic the oxidative stress state. We aimed to investigate whether AAPH can generate lung functional, inflammatory, histological and biochemical impairments in the lung. Wistar rats were divided into five groups and instilled with saline solution (714 µL/kg, CTRL group) or different amounts of AAPH (25, 50, 100, and 200 mg/kg, 714 µL/kg, AAPH groups). Seventy-two hours later the animals were anesthetized, paralyzed, intubated and static elastance (Est), viscoelastic component of elastance (ΔE), resistive (ΔP1) and viscoelastic (ΔP2) pressures were measured. Oxidative damage, inflammatory markers and lung morphometry were analyzed. ΔP1 and Est were significantly higher in AAPH100 and AAPH200 than in the other groups. The bronchoconstriction indexes were larger in AAPH groups than in CTRL. The area occupied by collagen and elastic fibers, polymorpho- and mononuclear cells, malondialdehyde and carbonyl groups levels were significantly higher in AAPH200 than in CTRL. In comparison to CTRL, AAPH200 showed significant decrease and increase in the activities of superoxide dismutase and catalase, respectively. AAPH augmented the release of pro-inflammatory cytokines IL-1ß, IL-6 e TNF-α. Hence, exposure to AAPH caused significant inflammatory alterations and redox imbalance accompanied by altered lung mechanics and histology. Furthermore, we disclosed that exposure to AAPH may represent a useful in vivo tool to trigger lung lesions.
RESUMEN
We compared the toxicity of subchronic exposure to equivalent masses of particles from sugar cane burning and traffic. BALB/c mice received 3 intranasal instillations/week during 1, 2 or 4 weeks of either distilled water (C1, C2, C4) or particles (15µg) from traffic (UP1, UP2, UP4) or biomass burning (BP1, BP2, BP4). Lung mechanics, histology and oxidative stress were analyzed 24h after the last instillation. In all instances UP and BP groups presented worse pulmonary elastance, airway and tissue resistance, alveolar collapse, bronchoconstriction and macrophage influx into the lungs than controls. UP4, BP2 and BP4 presented more alveolar collapse than UP1 and BP1, respectively. UP and BP had worse bronchial and alveolar lesion scores than their controls; BP4 had greater bronchial lesion scores than UP4. Catalase was higher in UP4 and BP4 than in C4. In conclusion, biomass particles were more toxic than those from traffic after repeated exposures.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Exposición por Inhalación , Pulmón/patología , Material Particulado/toxicidad , Trastornos Respiratorios/inducido químicamente , Saccharum/química , Animales , Bronquios/patología , Líquido del Lavado Bronquioalveolar , Catalasa/metabolismo , Femenino , Galectina 3/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula , Estadísticas no Paramétricas , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de TiempoRESUMEN
Environmentally relevant doses of inhaled diesel particles elicit pulmonary inflammation and impair lung mechanics. Eugenol, a methoxyphenol component of clove oil, presents in vitro and in vivo anti-inflammatory and antioxidant properties. Our aim was to examine a possible protective role of eugenol against lung injuries induced by diesel particles. Male BALB/c mice were divided into four groups. Mice received saline (10 µl in; CTRL group) or 15 µg of diesel particles DEP (15 µg in; DIE and DEUG groups). After 1 h, mice received saline (10 µl; CTRL and DIE groups) or eugenol (164 mg/kg; EUG and DEUG group) by gavage. Twenty-four hours after gavage, pulmonary resistive (ΔP1), viscoelastic (ΔP2) and total (ΔPtot) pressures, static elastance (Est), and viscoelastic component of elastance (ΔE) were measured. We also determined the fraction areas of normal and collapsed alveoli, amounts of polymorpho- (PMN) and mononuclear cells in lung parenchyma, apoptosis, and oxidative stress. Est, ΔP2, ΔPtot, and ΔE were significantly higher in the DIE than in the other groups. DIE also showed significantly more PMN, airspace collapse, and apoptosis than the other groups. However, no beneficial effect on lipid peroxidation was observed in DEUG group. In conclusion, eugenol avoided changes in lung mechanics, pulmonary inflammation, and alveolar collapse elicited by diesel particles. It attenuated the activation signal of caspase-3 by DEP, but apoptosis evaluated by TUNEL was avoided. Finally, it could not avoid oxidative stress as indicated by malondialdehyde.
Asunto(s)
Eugenol/farmacología , Pulmón/efectos de los fármacos , Neumonía/inducido químicamente , Neumonía/tratamiento farmacológico , Alveolos Pulmonares/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Etiquetado Corte-Fin in Situ/métodos , Peroxidación de Lípido/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Neumonía/metabolismo , Neumonía/patología , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , Mecánica Respiratoria/efectos de los fármacosRESUMEN
Lung mechanics, histology, oxygenation and type-III procollagen (PCIII) mRNA were studied aiming to evaluate the need to readjust ventilatory pattern when going from two- to one-lung ventilation (OLV). Wistar rats were assigned to three groups: the left lung was not ventilated while the right lung received: (1) tidal volume (V(T))=5 ml/kg and positive end-expiratory pressure (PEEP)=2 cm H(2)O (V5P2), (2) V(T)=10 ml/kg and PEEP=2 cm H(2)O (V10P2), and (3) V(T)=5 ml/kg and PEEP=5 cm H(2)O (V5P5). At 1-h ventilation, V5P2 showed hypoxemia, alveolar collapse and impaired lung function. Higher PEEP minimized these changes and prevented hypoxemia. Although high V(T) prevented hypoxemia and maintained a higher specific compliance than V5P2, a morphologically inhomogeneous parenchyma and higher PCIII expression resulted. In conclusion, the association of low V(T) and an adequate PEEP level could be useful to maintain arterial oxygenation without inducing a possible inflammatory/remodeling response.
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Respiración con Presión Positiva/métodos , Ventilación Pulmonar/fisiología , Mecánica Respiratoria/fisiología , Animales , Masculino , Ratas , Ratas Wistar , Volumen de Ventilación PulmonarRESUMEN
Cyanobacterial blooms that generate microcystins (MCYSTs) are increasingly recognized as an important health problem in aquatic ecosystems. We have previously reported the impairment of pulmonary structure and function by microcystin-LR (MCYST-LR) exposure as well as the pulmonary improvement by intraperitoneally injected (i.p.) LASSBio 596. In the present study, we aimed to evaluate the usefulness of LASSBio 596 per os on the treatment of pulmonary and hepatic injuries induced by MCYST-LR. Swiss mice received an intraperitoneal injection of 40 µl of saline (CTRL) or a sub-lethal dose of MCYST-LR (40 µg/kg). After 6 h the animals received either saline (TOX and CTRL groups) or LASSBio 596 (50 mg/kg, LASS group) by gavage. Eight hours after the first instillation, lung impedance (static elastance, elastic component of viscoelasticity and resistive, viscoelastic and total pressures) was determined by the end-inflation occlusion method. Left lung and liver were prepared for histology. In lung and hepatic homogenates MCYST-LR, TNF-α, IL-1ß and IL-6 were determined by ELISA. LASSBio 596 per os (LASS mice) kept all lung mechanical parameters, polymorphonuclear (PMN) cells, pro-inflammatory mediators, and alveolar collapse similar to control mice (CTRL), whereas in TOX these findings were higher than CTRL. Likewise, liver structural deterioration (hepatocytes inflammation, necrosis and steatosis) and inflammatory process (high levels of pro-inflammatory mediators) were less evident in the LASS than TOX group. LASS and CTRL did not differ in any parameters studied. In conclusion, orally administered LASSBio 596 prevented lung and hepatic inflammation and completely blocked pulmonary functional and morphological changes induced by MCYST-LR.
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Antiinflamatorios no Esteroideos/administración & dosificación , Toxinas Bacterianas/antagonistas & inhibidores , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Microcistinas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/administración & dosificación , Ftalimidas/administración & dosificación , Neumonía/prevención & control , Administración Oral , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Toxinas Bacterianas/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Mediadores de Inflamación/metabolismo , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Toxinas Marinas/antagonistas & inhibidores , Toxinas Marinas/toxicidad , Ratones , Microcistinas/toxicidad , Infiltración Neutrófila/efectos de los fármacos , Inhibidores de Fosfodiesterasa/uso terapéutico , Ácidos Ftálicos , Ftalimidas/uso terapéutico , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/patología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , Distribución Aleatoria , SulfonamidasRESUMEN
The treatment of microcystin-LR (MCYST-LR)-induced lung inflammation has never been reported. Hence, LASSBio 596, an anti-inflammatory drug candidate, designed as symbiotic agent that modulates TNF-alpha levels and inhibits phosphodiesterase types 4 and 5, or dexamethasone were tested in this condition. Swiss mice were intraperitoneally (i.p.) injected with 60 microl of saline (CTRL) or a sub-lethal dose of MCYST-LR (40 micrg/kg). 6 h later they were treated (i.p.) with saline (TOX), LASSBio 596 (10 mg/kg, L596), or dexamethasone (1 mg/kg, 0.1 mL, DEXA). 8 h after MCYST-LR injection, pulmonary mechanics were determined, and lungs and livers prepared for histopathology, biochemical analysis and quantification of MCYST-LR. TOX showed significantly higher lung impedance than CTRL and L596, which were similar. DEXA could only partially block the mechanical alterations. In both TOX and DEXA alveolar collapse and inflammatory cell influx were higher than in CTRL and L596, being LASSBio 596 more effective than dexamethasone. TOX showed oxidative stress that was not present in CTRL and L596, while DEXA was partially efficient. MCYST-LR was detected in the livers of all mice receiving MCYST-LR and no recovery was apparent. In conclusion, LASSBio 596 was more efficient than dexamethasone in reducing the pulmonary functional impairment induced by MCYST-LR.
Asunto(s)
Antiinflamatorios/uso terapéutico , Toxinas Bacterianas/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Dexametasona/uso terapéutico , Microcistinas/toxicidad , Ftalimidas/uso terapéutico , Neumonía/tratamiento farmacológico , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Masculino , Toxinas Marinas , Ratones , Ácidos Ftálicos , Neumonía/inducido químicamente , Neumonía/patología , SulfonamidasRESUMEN
Dexmedetomidine is a highly selective and specific alpha(2)-adrenergic agonist, with sedative, analgesic, and sympatholytic activities. The aim of the present study was to define the effects of DMED in respiratory mechanics in normal rats. In addition, lung morphometry was studied to determine whether the physiological changes reflected underlying morphological changes defining the sites of action of dexmedetomidine. Arterial blood gases were also determined. Twelve adult Wistar rats were randomly assigned to two groups of six animals each: PENTO and DMED. In PENTO group animals were sedated (diazepam, 5mg, i.p.) and anaesthetised with pentobarbital sodium (20mgkg(-1) i.p.). The rats of the DMED group received dexmedetomidine (250mugkg(-1) i.p. followed by intravenous infusion of 0.5mugkg(-1)h(-1)). In spontaneously breathing rats, minute ventilation, respiratory frequency, and neuromuscular inspiratory drive were lower in dexmedetomidine group, which also presented hypercapnia, whereas tidal volume, inspiratory, expiratory, and total respiratory cycle times were higher in dexmedetomidine group compared to the PENTO group. During mechanical ventilation, respiratory mechanical parameters were similar in both groups. These findings were supported by the absence of histological changes. In conclusion, under the conditions studied, dexmedetomidine did not change respiratory mechanical parameters and lung histology, but induced ventilatory depression.