RESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory response of the airways and lungs to noxious particles and gases, mostly cigarette smoke (CS). Pathological changes characteristic of COPD include airway wall thickening, peribronchial fibrosis, peribronchial lymphoid follicles and destruction of lung parenchyma (emphysema). The recruitment of inflammatory cells into the lung in response to CS is thought to play an important role in the development of COPD. OBJECTIVE: Our aim was to study the contribution of chemokine receptor 5 (CCR5) to the pathogenesis of COPD and specifically whether the development of airway remodelling is a direct result of airway inflammation or rather occurs through an independent mechanism. METHODS: In this study, C57BL/6 wild-type mice and CCR5-deficient mice were subjected to sub-acute (4 weeks) and chronic (24 weeks) CS exposure. RESULTS: Both sub-acute and chronic CS exposure significantly increased CCR5 mRNA expression and protein levels of CCR5 ligands [macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta and regulated upon activation, normal T expressed and secreted (RANTES)], and induced the recruitment of neutrophils, macrophages, dendritic cells, and lymphocytes to the bronchoalveolar lavage (BAL) of wild-type mice. Chronic CS exposure also increased the number and extent of peribronchial lymphoid follicles. In CCR5 knockout (KO) mice, these CS-induced increases in CCR5 ligands, inflammatory cells in BAL and peribronchial lymphoid follicles were all significantly attenuated compared with wild-type animals. Importantly, chronic CS exposure induced airspace enlargement in wild-type mice, while CCR5 KO mice were partially protected against the development of emphysema. However, CCR5 deficiency did not affect CS-induced airway wall remodelling, because chronic CS exposure induced a similar increase in airway wall thickness, smooth muscle mass and peribronchial deposition of collagen and fibronectin in both wild-type and CCR5 KO mice. CONCLUSION: Our data suggest that CCR5 contributes to pulmonary inflammation and to the development of emphysema in response to CS. CCR5 is, however, not implicated in CS-induced airway wall remodelling, suggesting that the mechanisms that lead to airway inflammation are distinct to those responsible for airway remodelling.
Asunto(s)
Enfisema Pulmonar/inmunología , Enfisema Pulmonar/patología , Receptores CCR5/deficiencia , Fumar , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/análisis , Citocinas/metabolismo , Ratones , Ratones Noqueados , Neumonía/inmunología , Neumonía/patología , Enfisema Pulmonar/genética , Receptores CCR5/genéticaRESUMEN
Non-specific anti-inflammatory medication is actually the treatment of choice for controlling the T-helper type 2 (Th-2) cell-driven airway inflammation in asthma. The induction of counterbalancing Th-1 cell clones, long considered a promising approach for immunotherapy, has failed to fulfil its promise because of potentially detrimental side-effects. This is therefore probably not a valid option for the treatment of asthma. With the increasing awareness that active immune mechanisms exist to control inflammatory responses, interest rises to investigate whether these can be exploited to control allergen-induced airway disease. The induction of antigen-specific T cells with suppressive characteristics (regulatory T cells) is therefore a potentially interesting approach. These regulatory T cells mediate tolerance in healthy, non-atopic individuals and have the potential of becoming an effective means of preventing allergen-induced airway inflammation and possibly of suppressing ongoing allergic immune responses. Here we review the available knowledge about allergen-induced suppressive immunity obtained from animal models taking into account the different developmental stages of allergic airway disease.
Asunto(s)
Traslado Adoptivo/métodos , Asma/terapia , Modelos Animales de Enfermedad , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Alérgenos/administración & dosificación , Animales , Asma/inmunología , Humanos , Tolerancia Inmunológica , RatonesRESUMEN
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, that is not fully reversible, and that is associated with an abnormal inflammatory response of the airways and lungs to noxious particles and gases. The airflow limitation is caused by increased resistance of the small conducting airways and by decreased elastic recoil forces of the lung due to emphysematous destruction of the lung parenchyma. In vivo animal models can help to unravel the molecular and cellular mechanisms underlying the pathogenesis of COPD. Mice represent the most favored animal species with regard to the study of (both innate and adaptive) immune mechanisms, since they offer the opportunity to manipulate gene expression. Several experimental approaches are applied in order to mimic the different traits of COPD in these murine models. Firstly, the tracheal instillation of tissue-degrading enzymes induces emphysema-like lesions in the lung parenchyma, adding further proof to the protease-antiprotease imbalance hypothesis. Secondly, the inhalation of noxious stimuli, including tobacco smoke, sulfur dioxide, nitrogen dioxide, or oxidants such as ozone, may also lead to COPD-like lesions in mice, depending on concentration, duration of exposure and strainspecific genetic susceptibility. Thirdly, in transgenic mice, a specific gene is either overexpressed (non-specific or organ-specific) or selectively depleted (constitutively or conditionally). The study of these transgenic mice, either per se or in combination with the above mentioned experimental approaches (e.g. the inhalation of tobacco smoke), can offer valuable information on both the physiological function of the gene of interest as well as the pathophysiological mechanisms of diseases with complex traits such as COPD.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Animales , Humanos , Ratones , Ratones Transgénicos , Enfermedad Pulmonar Obstructiva Crónica/genéticaRESUMEN
OBJECTIVES: To evaluate children with refractory monosymptomatic nocturnal enuresis to determine whether detrusor overactivity (DOA) plays a role in 4 weeks of unsuccessful treatment with retention control training (RCT); whether an increase in bladder capacity can eventually be obtained by RCT plus oxybutynin; and whether the increase in capacity is the primary key to success. METHODS: Sixty-eight children with refractory monosymptomatic nocturnal enuresis were included. They all had a maximal cystometric capacity less than the age-expected value. RCT was done by water loading and retention to the point of urgency once daily. During training, changes in bladder capacity were evaluated by voiding charts. If after 4 weeks of RCT, less than a 10% increase in bladder capacity was noted, oral oxybutynin was added. RESULTS: The incidence of DOA was 66%. After 4 weeks of RCT, the bladder capacity increased in 20.6%. Combining RCT with oxybutynin led in the end to normalization of the bladder capacity in 79.4%. Older age and high-pressure DOA negatively influenced the ability to increase the bladder capacity. Fifteen children became completely dry, mainly by converting enuresis to nocturia. CONCLUSIONS: Unsuccessful RCT is often caused by DOA, especially if a bladder capacity rise of at least 10% cannot be achieved within 4 weeks. If oxybutynin is added to the treatment, normalization of bladder capacity can be obtained in most. This increased bladder capacity cures enuresis only in a minority by sharpening their arousal and provoking nocturia.