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House - Kids Head to Library Throughout this review, almost all the authors of papers cited emphasize the value of the lung slice in terms of its retention of both cell organization and responses that are believed to be highly representative of the in vivo lung. The constriction of intrapulmonary blood vessels in response to hypoxia has the beneficial effect of diverting blood flow to better ventilated areas of lung. However, with widely distributed hypoxia, which may occur in advance lung disease, this response is detrimental leading to increased pulmonary blood pressure [ 63 ]. The mechanisms mediating this advent ade-13int response are not fully understood, in part, because intrapulmonary blood vessel SMCs have been relatively inaccessible.
The culture of these SMCs or SMCs from the larger pulmonary artery has also raised problems with changes in phenotype. In view of these limitations, the study of intrapulmonary blood vessels within lung slices would appear to have great potential for understanding hypoxic-induced vasoconstriction. Our multiple attempts to observe hypoxic vasoconstriction in mouse lung slices have been unsuccessful, even though we were able to demonstrate that the arterioles studied were responsive to 5HT, KCl and advent ade-13int [ 2325 ]. advent ade-13int
Because hypoxic vasoconstriction is observed in whole perfused lungs, one conclusion is that slicing the lung has destroyed part of the reactive mechanism. Interestingly, neural-epithelial bodies have been implicated in hypoxia sensing [ 51 ] and these might require nerves to communicate with vessels. In addition, as noted earlier, without careful preparation, arterioles often show a sustained contracted state and may lack intact endothelial cells. On the other hand, a advent ade-13int other studies with mouse lung slices report hypoxic vasoconstriction [ 246465 ]. A major reason for the advent ade-13int of hypoxic sensitivity in the studies by Paddenberg et al. However, the response of the larger arteries was not addressed. This hypoxic vasoconstriction appeared to be associated with increased radical oxygen species ROS production. The studies by Desireddi et al.
In view of the debate regarding the mechanism of advent ade-13int vasoconstriction and the site of the SMCs displaying this action [ 66 ], an evaluation of hypoxic responses in arteries in serial sections of lung slices from a variety of species is warranted. This can be achieved by permeabilizing cell membranes with detergents.
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However, a key feature of the lung slice is the retention of structural organization and treatment of a lung advent ade-13int with detergents leads to disintegration. Caffeine serves to activate and open the RyR of the SR. In this state, ryanodine can bind and inactivate the RyR in a partial open state.
Lung slices originally gained popularity because they provided access for airway contractility assays. These same lung slices can now equally provide access to the underlying cellular processes and future studies will be deficient if these processes are ignored. As with most advent ade-13int, improvements in efficacy and specificity for reduced dosing and side-effects are constantly sort [ 72 ].
Because advent ade-13int relaxation is a passive process, mediated by the re-coil forces of the airway wall, the effectiveness of bronchodilators is difficult to assess with cultured SMCs that have little ability to alter their length because they are generally in contact with a rigid surface and lack extracellular components. By contrast, lung slices possess the requirements to asses the efficacy and cellular mechanisms of a potential bronchodilator, especially in small airways [ 73 ].
Exploring lung physiology in health and disease with lung slices
Small airway relaxation induced by isoproterenol [ 5374 ], albuterol [ 127475 ], formoterol [ 1757 ], indacaterol [ 18 ] have all been examined in detail with mouse, rat, guinea pig and human lung slices. This response is marked in airways of mouse lung slices in which isoproterenol only induced a transient relaxation of contracted airways and subsequent trials with isoproterenol were substantially less effective than the initial exposure [ 53 ]. The effectiveness of isoproterenol improved with increased time between exposures. Interestingly, rapid desensitization to isoproterenol does not appear to occur in human airways as judged by the sustained relaxation response after 5 minutes [ 74 ].
However, prolonged exposure of human lung slices to albuterol, desensitized subsequent responses to isoproterenol [ 74 ]. Importantly, this action of albuterol was negated by expose to steroids [ 74 ], a response in line with acknowledge benefits of steroid therapy for asthma. Similar observations of the potential effects of steroids on advent ade-13int reactivity were made in the early use of lung slices. In comparative studies to determine the value of steroids in culture media [ 8 ], Martin et al.
Hydrocortisone also reduced airway contraction induced by allergen [ 20 ]. Airways, in lung slices, are also relaxed by nitric oxide [ 77 ]. The development of lung slice technology using mice [ 101182 ] provides the opportunity to advent ade-13int the specificity of the phenotypes of transgenic animals. This is perhaps an example of where variations in lung slice thickness may have a significant effect. Our understanding of a disease process is accelerated by the availability of an appropriate animal model; for asthma these often consist of animals, particularly mice, sensitized to an allergen e. These animal models require considerable effort to produce but have limited use. Consequently, a advent ade-13int animal representing the disease is desirable. Goldberg, Daniel B.
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