RESUMEN
Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.
Asunto(s)
Pulmón/fisiopatología , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Receptores de Leptina/genética , Adulto , Alelos , Animales , Femenino , Regulación de la Expresión Génica , Genotipo , Humanos , Inmunohistoquímica , Pulmón/metabolismo , Masculino , Ratones , Persona de Mediana EdadRESUMEN
BACKGROUND: Subanaesthetic concentrations of volatile anaesthetics significantly affect the respiratory response to hypoxia and hypercapnoeia. Individuals with an inherited blunted respiratory drive are more affected than normal individuals. To test the hypothesis that subjects with blunted hypercapnoeic respiratory drive are diversely affected by different anaesthetics, we studied the effects of three volatile anaesthetics on the control of breathing in C3H/HeJ (C3) mice, characterized by a blunted hypercapnoeic respiratory response. METHODS: Using whole body plethysmography, we assessed respiratory rate (RR) and pressure amplitude in 11 male C3 mice at rest, during anaesthesia with isoflurane, sevoflurane or desflurane, and during recovery. To test respiratory drive, mice were exposed to 8% carbon dioxide. Data were analysed by two-way-analysis of variance with post hoc tests and Bonferroni correction. RESULTS: RR was unaffected during sevoflurane anaesthesia up to 1.0 MAC. Likewise, sevoflurane at 1.5 MAC affected RR less than either isoflurane (P=0.0014) or desflurane (P=0.0048). The increased RR to a carbon dioxide challenge was blocked by all three anaesthetics even at the lowest concentration, and remained depressed during recovery (P<0.0001). Tidal volume was unaffected by all three anaesthetics. CONCLUSIONS: In C3 mice, spontaneous ventilation was less affected during sevoflurane compared with either isoflurane or desflurane anaesthesia. However, the RR response to hypercapnoeia was abolished at 0.5 MAC for all the anaesthetic agents and remained depressed even at the end of recovery. Our data suggest that different volatile anaesthetics have varying effects on the control of breathing frequency but all block the respiratory response to carbon dioxide. Therefore, a genetic predisposition to a blunted carbon dioxide response represents a susceptibility factor that interacts with hypercapnoeic hypoventilation during maintenance of anaesthesia and in the emergence from anaesthesia, regardless of the agent used.
Asunto(s)
Anestésicos por Inhalación/farmacología , Hipercapnia/fisiopatología , Isoflurano/análogos & derivados , Respiración/efectos de los fármacos , Animales , Desflurano , Predisposición Genética a la Enfermedad , Isoflurano/farmacología , Masculino , Éteres Metílicos/farmacología , Ratones , Ratones Endogámicos C3H , Pletismografía Total , Sevoflurano , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
BACKGROUND: Postanaesthetic hypoxia and ischaemia can lead to postoperative morbidity and mortality. We studied the effect of isoflurane anaesthesia in two inbred mouse strains known for phenotypic differences in breathing pattern and respiratory drive during carbon dioxide challenge and their first-generation offspring (F(1)). METHODS: Using whole body plethysmography, we assessed respiratory rate (RR) and pressure amplitude (Amp) in male B6 (high responder to hypercapnia), C3 (low responder), and F(1) mice at rest, during anaesthesia with isoflurane, and during recovery from anaesthesia. At each time point, the magnitude and pattern of breathing were determined during hypercapnic challenge (FI(CO(2)) = 0.08). Data (mean (SD)) were analysed by generalized ANOVA with post hoc Bonferroni's correction (P<0.05). RESULTS: During isoflurane anaesthesia, strain differences between B6 and C3 mice in RR were obscured while differences in Amp persisted. In contrast to baseline RR responses to carbon dioxide were significantly reduced at 0.5 MAC (increase in RR: 175 (33) bpm, 147 (44) bpm, 127 (33) bpm, for B6, C3, and F(1) strains respectively) and completely blocked at 1.5 MAC (change in RR: -3 (10) bpm, -2 (1) bpm, -4 (5) bpm, for B6, C3, and F(1) strains, respectively). During recovery, B6 mice showed a significant increase in RR (77 (33) bpm; P<0.0001) as well as in Amp. This was not observed in either C3 (-22 (31) bpm) or F(1) mice (23 (51) bpm). CONCLUSION: Isoflurane anaesthesia abolished the strain differences in respiratory drive between B6, C3, and F(1) mice. However, during recovery from anaesthesia, significant strain variation in respiratory drive reappeared and was more pronounced compared with pre-anaesthetic levels. These results suggested, that genetic differences may have minimal contribution to decreased respiratory drive during anaesthesia, but may be a major risk factor for post-operative hypoventilation and the associated morbidity and mortality.
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Anestesia/métodos , Anestésicos por Inhalación/farmacología , Dióxido de Carbono/farmacología , Isoflurano/farmacología , Respiración/efectos de los fármacos , Animales , Dióxido de Carbono/sangre , Femenino , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Fenotipo , Pletismografía Total/métodos , Respiración/genética , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
We hypothesized that upper airway obstruction (UAO) leads to a compensatory increase in the duty cycle [ratio of inspiratory time to respiratory cycle length (Ti/Tt)], which is determined by genetic factors. We examined the compensatory Ti/Tt responses to 1). UAO and hypercapnia among normal individuals and 2). hypercapnia in different inbred strains, C3H/HeJ (C3) and C57BL/6J (B6), and their first- and second-generation (F2) offspring. 3). We then used the compensatory Ti/Tt response in the F2 to determine genetic linkage to the mouse genome. First, normal individuals exhibited a similar increase in the Ti/Tt during periods of hypercapnia (0.11 +/- 0.07) and UAO (0.09 +/- 0.06) compared with unobstructed breathing (P < 0.01). Second, the F2 offspring of C3 and B6 progenitors showed an average Ti/Tt response to 3% CO2 (0.42 +/- 0.005%) that was significantly (P < 0.01) greater than that of the two progenitors. Third, with a peak log of the odds ratio score of 4.4, Ti/Tt responses of F2 offspring are genetically linked to an interval between 58 and 64 centimorgans (cM) on mouse chromosome 5. One gene in the interval, Dagk4 at 57 cM, is polymorphic for C3 and B6 mice. Two other genes, Adrbk2 at 60 cM and Nos1 at 65 cM, have biological plausibility in mechanisms of upper airway patency and chemosensitivity, respectively. In summary, Ti/Tt may serve as an intermediate physiological phenotype for compensatory neuromuscular response mechanisms for maintaining ventilation in the face of UAO and hypoventilation and to help target specific candidate genes that may play a role in the expression of sleep-disordered breathing.
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Cromosomas/genética , Cromosomas/fisiología , Hipercapnia/genética , Hipercapnia/fisiopatología , Mecánica Respiratoria/genética , Mecánica Respiratoria/fisiología , Adulto , Presión del Aire , Obstrucción de las Vías Aéreas/genética , Obstrucción de las Vías Aéreas/fisiopatología , Animales , ADN/genética , Femenino , Ligamiento Genético/genética , Marcadores Genéticos , Genotipo , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Fenotipo , Pletismografía Total , Polisomnografía , Valores de Referencia , Apnea Obstructiva del Sueño/genética , Apnea Obstructiva del Sueño/fisiopatología , Especificidad de la EspecieAsunto(s)
Regulación de la Expresión Génica , Variación Genética , Ventilación Pulmonar/genética , Receptores AMPA/genética , Animales , Tronco Encefálico/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Pletismografía Total , Ventilación Pulmonar/fisiología , Análisis de Secuencia de ADN , Factores de TiempoRESUMEN
Obese females are less predisposed to sleep-disordered breathing and have higher serum leptin levels than males of comparable body weight. Because leptin is a powerful respiratory stimulant, especially during sleep, we hypothesized that the elevated leptin level is necessary to maintain normal ventilatory control in obese females. We examined ventilatory control during sleep and wakefulness in male and female leptin-deficient obese C57BL/6J-Lep(ob) mice, wild-type C57BL/6J mice with dietary-induced obesity and high serum leptin levels, and normal weight wild-type C57BL/6J mice. Both male and female C57BL/6J-Lep(ob) mice had depressed hypercapnic ventilatory response (HCVR) in comparison with wild-type animals. In comparison with male C57BL/6J-Lep(ob) mice, female C57BL/6J-Lep(ob) mice had reduced HCVR and respiratory drive (a ratio of tidal volume to inspiratory time) both during non-rapid eye movement (NREM) sleep and wakefulness. In contrast, the HCVR did not differ between sexes in wild-type mice during NREM sleep and wakefulness, but was lower in females during REM sleep. Thus, leptin deficiency in female obesity is even more detrimental to hypercapnic ventilatory control during wakefulness and NREM sleep than in obese, leptin-deficient males.
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Leptina/deficiencia , Obesidad/complicaciones , Insuficiencia Respiratoria/etiología , Animales , Dióxido de Carbono , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Obesidad/metabolismo , Obesidad/fisiopatología , Insuficiencia Respiratoria/fisiopatología , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
Appointing physiological function to specific genetic determinants requires a systems physiologist to consider ways of assessing precise phenotypic mechanisms. The integration of ventilation, metabolism and thermoregulation, for example, is very complex and may differ among small and large mammalian species. This challenge is particularly applicable to the study of short- and long-term adaptation of these systems to hypoxic exposure associated with high altitude. Our laboratory has initiated a research effort to dissect the complexity of hypoxic adaptation using traditional quantitative genetic analysis and contemporary DNA genotyping techniques. Although the current evidence in murine models demonstrates that specific genes influence control of hypoxic ventilatory responses (HVR), the relevance of these determinants to human adaptation to altitude remains open to exploration. Our review discusses the progress and uncertainties associated with assigning a genetic basis to variation in acute and chronic HVR.
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Adaptación Fisiológica/genética , Modelos Animales de Enfermedad , Hipoxia/fisiopatología , Ventilación Pulmonar/genética , Animales , Humanos , Ratones , Proyectos de InvestigaciónRESUMEN
Insulin-dependent diabetes mellitus (IDDM) can lead to ventilatory depression and decreased sensitivity to hypercapnia. We examined relationships between ventilation, plasma insulin, leptin, ketones, and blood glucose levels in two mouse models of IDDM: (1) streptozotocin-induced diabetes in C57BL/6J mice on a regular diet or with induced obesity from a high fat diet; and (2) spontaneous diabetes mellitus in NOD-Ltj mice. In both mouse models, IDDM resulted in depression of the hypercapnic ventilatory response (HCVR). This ventilatory depression was not associated with decreases in plasma insulin or leptin levels. There was, however, a strong association between the duration of hyperglycemia, the decline in HCVR, and increased glycosylation of the diaphragm. Hyperventilation was observed in only six of 14 C57BL/6J obese wild-type mice, despite a significant degree of diabetic ketoacidosis (DKA) in all 14 animals. In mice with DKA, there was a significant correlation between the increase in baseline minute ventilation (V E) and hyperleptinemia (r = 0.77, p < 0.01). In leptin-deficient C57BL/6J-Lep(ob) mice, low levels of both V E and ketones were observed. These results suggest that: (1) depression of the HCVR in IDDM is associated with hyperglycemia and glycosylation of the diaphragm; and (2) the hyperventilation of DKA is leptin dependent.
Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Ventilación Pulmonar/fisiología , Animales , Diabetes Mellitus Tipo 1/metabolismo , Dieta , Grasas de la Dieta , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Sueño , Factores de Tiempo , VigiliaRESUMEN
Genetic determinants confer variation among inbred mouse strains with respect to the magnitude and pattern of breathing during acute hypoxic challenge. Specifically, inheritance patterns derived from C3H/HeJ (C3) and C57BL/6J (B6) parental strains suggest that differences in hypoxic ventilatory response (HVR) are controlled by as few as two genes. The present study demonstrates that at least one genetic determinant is located on mouse chromosome 9. This genotype-phenotype association was established by phenotyping 52 B6C3F2 (F2) offspring for HVR characteristics. A genome-wide screen was performed using microsatellite DNA markers (n = 176) polymorphic between C3 and B6 mice. By computing log-likelihood values (LOD scores), linkage analysis compared marker genotypes with minute ventilation (&Vdot;E), tidal volume (VT), and mean inspiratory flow (VT/TI, where TI is inspiratory time) during acute hypoxic challenge (inspired O2 fraction = 0.10, inspired CO2 fraction = 0.03 in N2). A putative quantitative trait locus (QTL) positioned in the vicinity of D9Mit207 was significantly associated with hypoxic VE (LOD = 4.5), VT (LOD = 4.0), and VT/TI (LOD = 5.1). For each of the three HVR characteristics, the putative QTL explained more than 30% of the phenotypic variation among F(2) offspring. In conclusion, this genetic model of differential HVR characteristics demonstrates that a locus approximately 33 centimorgans from the centromere on mouse chromosome 9 confers a substantial proportion of the variance in VE, VT, and VT/TI during acute hypoxic challenge.
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Cromosomas/genética , Hipoxia/genética , Hipoxia/fisiopatología , Enfermedad Aguda , Animales , ADN/genética , ADN/aislamiento & purificación , Ligamiento Genético/genética , Marcadores Genéticos , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Fenotipo , Mecánica Respiratoria/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
An organism is thought to be in a dynamic state of homeostasis when each physiological and behavioral system reaches a delicate balance within the framework of other regulatory processes. Many biological systems target specific set-point variables and generate circadian patterns. In this article, we focus on specific measurements representative of two systems, namely deep-body temperature and activity counts. We examine data collected every 30 minutes in mice, assume there are underlying circadian patterns, and extend the approach presented in Brumback and Rice (1998, Journal of the American Statistical Association 93, 961-976) in order to obtain estimates in the presence of correlated data. We then assess homeostasis using these estimates and their statistical properties.
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Biometría/métodos , Ritmo Circadiano/fisiología , Homeostasis , Animales , Temperatura Corporal/fisiología , Interpretación Estadística de Datos , Ratones , Modelos Estadísticos , Actividad Motora/fisiologíaRESUMEN
Identification of the genetic loci underlying asthma in humans has been hampered by variability in clinical phenotype, uncontrolled environmental influences, and genetic heterogeneity. To circumvent these complications, the genetic regulation of asthma-associated phenotypes was studied in a murine model. We characterized the strain distribution patterns for the asthma-related phenotypes airway hyperresponsiveness (AHR), lung eosinophils, and ovalbumin (OVA)-specific serum immunoglobulin (Ig) E induced by allergen exposure protocols in A/J, AKR/J, BALB/cJ, C3H/HeJ, and C57BL/6J inbred strains and in (C3H/HeJ x A/J)F1 mice. Expression of AHR differed between strains and was sometimes discordant with lung eosinophils or serum IgE. Furthermore, we identified two distinct quantitative trait loci (QTL) for susceptibility to allergen-induced AHR, Abhr1 (allergen-induced bronchial hyperresponsiveness) (lod = 4. 2) and Abhr2 (lod = 3.7), on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice. In addition, a QTL on chromosome 7 was suggestive of linkage to this trait. These QTL differ from those we have previously found to control noninflammatory AHR in the same crosses. Elucidation of the genes underlying these QTL will facilitate the identification of biochemical pathways regulating AHR in animal models of asthma and may provide insights into the pathogenesis of human disease.
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Alérgenos/inmunología , Hiperreactividad Bronquial/genética , Carácter Cuantitativo Heredable , Animales , Mapeo Cromosómico , Ligamiento Genético , Genotipo , Humanos , Ratones , Ratones Endogámicos , Fenotipo , Especificidad de la EspecieRESUMEN
Inbred mice are routinely used as genetic models in lung biology. Among many phenotypic differences in lung function and structure, C3H/HeJ (C3) and C57BL/6J (B6) inbred mice also demonstrate a significantly different ventilatory pattern during acute hypoxic challenge. The present study rejects the hypothesis that a genomic basis for differential hypoxic ventilatory responses (HVR) is linked to loci which determine differential breathing pattern at baseline, while proposing an alternative genetic model for HVR variation. Twelve BXH recombinant inbred (RI) strains derived from C3 and B6 progenitors were examined to enumerate the genes regulating differential HVR. In each of 134 mice, HVR was assessed using whole-body plethysmography to measure tidal volume (VT) and breathing frequency (f). With respect to f during hypoxia, three distinct and reproducible phenotypes are evident in the BXH RI strain distribution pattern (SDP). The SDP for hypoxic f is consistent with the hypothesis that parental strain differences are regulated by two genes. Cosegregation analysis suggest that the genetic control of f during hypoxia differs from the genes which control differential baseline f. Although the genetic control of VT appears more complex, differences in the minute ventilation (VE) during hypoxia is determined by VT. Therefore, this study suggests that the phenotypic variation in HVR between C3 and B6 parental strains, especially related to f during hypoxia, is regulated by as few as two major genetic determinants.
Asunto(s)
Hipoxia/genética , Hipoxia/fisiopatología , Modelos Genéticos , Respiración/genética , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Fenotipo , Recombinación Genética , Especificidad de la Especie , Volumen de Ventilación Pulmonar/genética , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
Acutely lowering ambient O(2) tension increases ventilation in many mammalian species, including humans and mice. Inheritance patterns among kinships and between mouse strains suggest that a robust genetic influence determines individual hypoxic ventilatory responses (HVR). Here, we tested specific genetic hypotheses to describe the inheritance patterns of HVR phenotypes among two inbred mouse strains and their segregant and nonsegregant progeny. Using whole body plethysmography, we assessed the magnitude and pattern of ventilation in C3H/HeJ (C3) and C57BL/6J (B6) progenitor strains at baseline and during acute (3-5 min) hypoxic [mild hypercapnic hypoxia, inspired O(2) fraction (FI(O(2))) = 0.10] and normoxic (mild hypercapnic normoxia, FI(O(2)) = 0.21) inspirate challenges in mild hypercapnia (inspired CO(2) fraction = 0.03). First- and second-filial generations and two backcross progeny were also studied to assess response distributions of HVR phenotypes relative to the parental strains. Although the minute ventilation (VE) during hypoxia was comparable between the parental strains, breathing frequency (f) and tidal volume were significantly different; C3 mice demonstrated a slow, deep HVR relative to a rapid, shallow phenotype of B6 mice. The HVR profile in B6C3F(1)/J mice suggested that this offspring class represented a third phenotype, distinguishable from the parental strains. The distribution of HVR among backcross and intercross offspring suggested that the inheritance patterns for f and VE during mild hypercapnic hypoxia are consistent with models that incorporate two genetic determinants. These results further suggest that the quantitative genetic expression of alleles derived from C3 and B6 parental strains interact to significantly attenuate individual HVR in the first- and second-filial generations. In conclusion, the genetic control of HVR in this model was shown to exhibit a relatively simple genetic basis in terms of respiratory timing characteristics.
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Hipoxia/genética , Hipoxia/fisiopatología , Respiración/genética , Enfermedad Aguda , Animales , Segregación Cromosómica , Femenino , Hipercapnia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Fenotipo , Pletismografía Total , Volumen de Ventilación PulmonarRESUMEN
Leptin is a protein produced by adipose tissue that circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating. The importance of this single peptide is vividly demonstrated by the profound obesity exhibited by the ob/ob mouse (C57BL/6J-Lep(ob)) which is unable to produce functional leptin. The measurement of respiratory function in the ob/ob mouse shows that the profound obesity is associated with impaired respiratory mechanics and depressed respiratory control, particularly during sleep. Longitudinal studies and leptin replacement studies in the ob/ob mouse indicate that leptin may act as both as a growth factor in the lung and as a neurohumoral modulator of central respiratory control mechanisms. Moreover, wildtype mice with diet-induced obesity have normal respiratory function associated with markedly elevated leptin levels. Human obesity, similar to obesity in wildtype mice, also causes an elevation in circulating leptin. However, unlike the tight relationship between obesity and elevated leptin present in an inbred strain of wildtype mice, human obesity is associated with more variable leptin levels for a given degree of adiposity. Thus, the possibility exists that a relative deficiency in leptin, or a leptin resistance, may play a role in obesity-related breathing disorders such as obesity hypoventilation syndrome (OHS) or obstructive sleep apnea (OSA).
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Leptina/fisiología , Obesidad/fisiopatología , Fenómenos Fisiológicos Respiratorios , Animales , Humanos , Ratones , Ratones ObesosRESUMEN
Advances in human and mouse genomes are revolutionizing research in lung biology and pulmonary medicine. Genomic strategies are available that link functional variation to molecular structure, and these approaches are currently being applied to the study of ventilatory control mechanisms. In this review, the author discusses the functional data obtained from inbred murine models in which genetic mutations and polymorphisms play a role in altered breathing. At the conclusion of this review, the author emphasizes the relatively small number of studies that have incorporated the use of genomics to link differential ventilatory function to molecular structure.
Asunto(s)
Modelos Animales de Enfermedad , Ratones Endogámicos/genética , Respiración/genética , Animales , Genoma , Genoma Humano , Humanos , Ratones , Estructura Molecular , Mutación/genética , Fenotipo , Polimorfismo Genético/genética , Ratas , Ratas EndogámicasRESUMEN
Genetic determinants of lung structure and function have been demonstrated by differential phenotypes among inbred mice strains. For example, previous studies have reported phenotypic variation in baseline ventilatory measurements of standard inbred murine strains as well as segregant and nonsegregant offspring of C3H/HeJ (C3) and C57BL/6J (B6) progenitors. One purpose of the present study is to test the hypothesis that a genetic basis for differential baseline breathing pattern is due to variation in lung mechanical properties. Quasi-static pressure-volume curves were performed on standard and recombinant inbred strains to explore the interactive role of lung mechanics in determination of functional baseline ventilatory outcomes. At airway pressures between 0 and 30 cmH2O, lung volumes are significantly (P < 0.01) greater in C3 mice relative to the B6 and A/J strains. In addition, the B6C3F1/J offspring demonstrate lung mechanical properties significantly (P < 0.01) different from the C3 progenitor but not distinguishable from the B6 progenitor. With the use of recombinant inbred strains derived from C3 and B6 progenitors, cosegregation analysis between inspiratory timing and measurements of lung volume and compliance indicate that strain differences in baseline breathing pattern and pressure-volume relationships are not genetically associated. Although strain differences in lung volume and compliance between C3 and B6 mice are inheritable, this study supports a dissociation between differential inspiratory time at baseline, a trait linked to a putative genomic region on mouse chromosome 3, and differential lung mechanics among C3 and B6 progenitors and their progeny.
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Pulmón/fisiología , Mecánica Respiratoria/genética , Animales , Mediciones del Volumen Pulmonar , Masculino , Ratones , Ratones Endogámicos A , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Fenotipo , Pletismografía , Volumen Residual , Capacidad Pulmonar TotalRESUMEN
Acute and subacute exposure to ozone (O3) induces lung inflammation and hyperpermeability and causes epithelial injury of both upper (nasal) and lower airways. Mast cells are important regulatory cells in mice for each of these effects. Subacute and chronic O3 exposures cause epithelial injury and inflammation in terminal bronchioles and proximal alveoli. Little is known, however, about the mechanisms of injury. Because inflammatory processes may be linked to the pathogenesis of many airway diseases, it is critical to understand the underlying mechanisms that initiate and propagate these processes. We tested the hypothesis that mast cells mediate airway injury induced by chronic O3 exposure by comparing regional airway inflammation and epithelial injury as well as ventilatory responses in genetically mast cell-deficient mice (WBB6F1-KitW/KitW-v [KitW/KitW-v]) with those in (1) normal, mast cell-sufficient, congenic littermates (WBB6F1(-)+/+ [+/+]) and those in (2) KitW/KitW-v mice that were repleted with mast cells by bone marrow transplantation (BMT) from +/+ donors (KitW/KitW-v-BMT). Thus, three (different) groups of mice were used. The following experimental protocol was utilized to test this hypothesis. Animals from each treatment group (n = 4-6/group) were exposed to 0.26 parts per million (ppm) O3 8 hours/day and 5 days/week for durations of 1, 3, 14, 30, and 90 days. Between 8-hour exposures, mice were exposed continuously to 0.06 ppm O3. Age-matched mice were simultaneously exposed to filtered air (0.0 ppm O3) to serve as O3 controls. To evaluate reversibility of exposure-induced lesions, a set of mice from each genotypic group was exposed to air or O3 for 90 days and then placed in HEPA-filtered air for 35 days. After each period of exposure and after 35-day recovery, the nasal cavity and lungs of O3- and air-exposed mice from each group were evaluated for regional inflammation and permeability, epithelial proliferation, and ventilation pattern. Estimates of airway inflammation and hyperpermeability were obtained by analysis of cell differentials and total protein concentrations, respectively, in fluids obtained through use of bronchoalveolar lavage (BAL). Ozone exposure caused significantly greater increases in lung macrophages, epithelial cells, and polymorphonuclear leukocytes (PMNs) in mast cell-sufficient +/+ and KitW/KitW-v-BMT mice than in mast cell-deficient KitW/KitW-v mice. Comparable ozone exposure also elicited increases in lung lymphocytes and in total protein, but there were no significant differences in these two genotypic groups. Cell and total-protein responses in BAL fluid returned to control levels (that is, air exposure only) in all three groups of mice after a 35-day recovery period. The effects of O3 exposure on cell proliferation in the nose and lung were evaluated in the genotypic groups by counting the number of cells that incorporated bromodeoxyuridine (BrdU, a thymidine analog) into DNA. In the centriacinar region of the lung, DNA synthesis was increased significantly in O3-exposed +/+ and KitW/KitW-v-BMT mice, but not in KitW/KitW-v mice, compared with DNA synthesis in air controls. Epithelial proliferation remained significantly elevated or even increased in +/+ and KitW/KitW-v-BMT mice after O3 exposure. Nasal responses to O3 were also evaluated in these three genotypic groups of mice, and there were slight, although statistically significant, O3-exposure effects on the transitional epithelium. However, there were no differences among the groups up to an exposure of 90 days in duration. After a 35-day recovery period, epithelial cell proliferation in +/+ and KitW/KitW-v-BMT mice was greater than that in KitW/KitW-v mice. There were no significant exposure, genotype, or duration effects on baseline ventilation or responses to hypercapnic hypoxia in the three groups of mice exposed to air or O3. (ABSTRACT TRUNCATED)
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Mastocitos/efectos de los fármacos , Oxidantes Fotoquímicos/toxicidad , Ozono/toxicidad , Sistema Respiratorio/efectos de los fármacos , Análisis de Varianza , Animales , Líquido del Lavado Bronquioalveolar/citología , Relación Dosis-Respuesta a Droga , Inflamación/inducido químicamente , Masculino , Ratones , Ratones Congénicos , Mecánica RespiratoriaRESUMEN
Human obesity leads to an increase in respiratory demands. As obesity becomes more pronounced some individuals are unable to compensate, leading to elevated arterial carbon dioxide levels (PaCO2), alveolar hypoventilation, and increased cardiorespiratory morbidity and mortality (Pickwickian syndrome). The mechanisms that link obesity and hypoventilation are unknown, but thought to involve depression of central respiratory control mechanisms. Here we report that obese C57BL/6J-Lepob mice, which lack circulating leptin, also exhibit respiratory depression and elevated PaCO2 (> 10 mm Hg; p < 0. 0001). A role for leptin in restoring ventilation in these obese, mutant mice was investigated. Three days of leptin infusion (30 microg/d) markedly increased minute ventilation (V E) across all sleep/wake states, but particularly during rapid eye movement (REM) sleep when respiration was otherwise profoundly depressed. The effect of leptin was independent of food intake, weight, and CO2 production, indicating a reversal of hypoventilation by stimulation of central respiratory control centers. Furthermore, leptin replacement in mutant mice increased CO2 chemosensitivity during non-rapid eye movement (NREM) (4.0 +/- 0.5 to 5.6 +/- 0.4 ml/min/%CO2; p < 0.01) and REM (-0.1 +/- 0.5 to 3.0 +/- 0.8 ml/min/%CO2; p < 0.01) sleep. We also demonstrate in wild-type mice that ventilation is appropriately compensated when obesity is diet-induced and endogenous leptin levels are raised more than tenfold. These results suggest that leptin can prevent respiratory depression in obesity, but a deficiency in central nervous system (CNS) leptin levels or activity may induce hypoventilation and the Pickwickian syndrome in some obese subjects. O'Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, Smith PL. Leptin prevents respiratory depression in obesity.
Asunto(s)
Obesidad/fisiopatología , Proteínas/farmacología , Respiración/efectos de los fármacos , Animales , Arterias , Dióxido de Carbono/sangre , Dióxido de Carbono/fisiología , Hipercapnia/fisiopatología , Leptina , Masculino , Ratones , Ratones Endogámicos C57BL/genética , Ratones Mutantes/genética , Obesidad/sangre , Obesidad/genética , Proteínas/análisis , Proteínas/genéticaRESUMEN
A profile of respiratory complications has been associated with the onset and development of obesity in humans. Similar phenotypes have been routinely demonstrated in genetic animal models of obesity such as the ob mouse (C57BL/6J-Lepob). The objective of the present study was to test the hypothesis that a constellation of respiratory complications are attenuated with leptin (i.e., protein product of the ob gene) replacement. Daily leptin administration during a 6-wk period was conducted to control body weight of mutant ob mice similar to genotypic control groups. During the treatment period, repeated baseline ventilatory measurements were assessed by using whole body plethysmography while quasistatic pressure-volume curves were performed to further explore the role of leptin in improving lung mechanics. Diaphragmatic myosin heavy chain (MHC) isoform phenotype was examined to determine proportional changes in MHC composition. In room air, breathing frequency and minute ventilation were significantly (P < 0.01) different among ob treatment groups, suggesting that leptin opposed the development of a rapid breathing pattern observed in vehicle-treated ob mice. Quasistatic deflation curves indicated that the lung volume of leptin-treated ob mice was significantly (P < 0.05) greater relative to vehicle-treated ob mice at airway pressures between 0 and 30 cmH2O. Diaphragm MHC composition of leptin-treated ob mice was restored significantly (P < 0.05) to resemble the control phenotype. In this genetic mouse model of obesity, the results suggested that respiratory complications associated with the obese phenotype, including rapid breathing pattern at baseline, diminished lung compliance, and abnormal respiratory muscle adaptations, are attenuated with prolonged leptin treatment.