https://www.cell.com/trends/biotechnology/pdf/S0167-7799(08)00074-7.pdf

Biomedical applications of sheep models: from asthma to vaccines.

The mouse is an ideal species for investigation at the interface of lung biology and lung function. As detailed in this review, there are well-developed methods for the quantitative study of lung function in mice. These methods can be applied to mice in both terminal and nonterminal experiments. Terminal experimental approaches provide more detailed physiological information, but nonterminal measurements provide adequate data for certain experiments. In this review, we provide two examples of how these models can be used to further understanding of the primary pathobiology of airway responsiveness in both the absence and the presence of induced airway inflammation. The first model is a dissection of chromosomal loci linked to the variance in airway responsiveness observed in the absence of any manipulation to induce airway inflammation. The second model explores the role of T-cell costimulatory signals in the induction of airway hyperresponsiveness. As the number of mice with targeted deletions of effector genes or insertion of informative transgenes grows, additional examples are likely to accrue.

Mouse models of airway responsiveness: physiological basis of observed outcomes and analysis of selected examples using these outcome indicators.

Eosinophil degranulation is a characteristic feature of asthma and allergic rhinitis. However, degranulated eosinophils have not been convincingly demonstrated in the common mouse models of these airway diseases. This study uses eosinophil peroxidase (EPO) histochemistry and transmission electron microscopy (TEM) analysis to assess eosinophil degranulation in the airways of ovalbumin (OVA)-sensitized and challenged BALB/c and C57BL/6 mice. Using TEM we also examined mouse and human blood eosinophils after in vitro incubation with formyl-Met-Leu-Phe (fMLP) or phorbol myristate acetate (PMA). Although OVA exposure induced significant nasal and lung eosinophilia, we did not observe any of the known cellular processes by which eosinophils release their granule products, i.e., eosinophil cytolysis, piecemeal degranulation, and exocytosis. The occurrence of other allergen-induced degranulation events was ruled out because no difference in granule morphology was observed between lung-tissue eosinophils and blood or bone-marrow eosinophils from control animals. Accordingly, there was no detectable extracellular EPO in lung tissues of allergic mice. Similarly, mouse blood eosinophils remained nondegranulated in vitro in the presence of fMLP and PMA, whereas the same treatment of human eosinophils resulted in extensive degranulation. This investigation indicates that OVA-induced airway inflammation in the present mouse strains does not involve significant eosinophil degranulation. It is speculated that this dissimilarity from the human disease may be due to a fundamental difference in the regulation of mouse and human eosinophils.

Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation.

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(97)01042-0.pdf

Eosinophil lysis and free granules: an in vivo paradigm for cell activation and drug development

Compositions and methods for the treatment and diagnosis of diseases or conditions amenable to treatment through modulation of expression of a gene encoding a p38 mitogen-activated protein kinase (p38 MAPK) are provided. Methods for the treatment and diagnosis of diseases or conditions associated with aberrant expression of one or more p38 MAPKs are also provided.

Antisense Modulation of P38 Mitogen Activated Protein Kinase Expression

Asthma in man has long been an ill-defined disease of uncertain aetiology, and is well-known to include a multitude of complex cellular and molecular interactions, involving numerous mediators, cytokines and chemokines. However, there appears to be an increasing acceptance that the non-specific airway hyperresponsiveness, which is the hallmark of asthma, occurs as a result of damage caused by the accumulation of large numbers of activated eosinophils within the airway wall [1,2]. Although the eosinophils are considered to be the major effector cells in the disease there is abundant evidence that the production, recruitment, activation and survival of these cells in airway tissues are orchestrated by cytokines produced by CD4'^ T lymphocytes of the TH2-like subtype [3]. A growing dilemma for those of us interested in the discovery and development of new drugs for the treatment of asthma is that the more we learn about the pathophysiology of this increasingly complex disease, the more difficult it has become to identify the critical molecular target, or targets, which may provide new opportunities for therapeutic intervention. One potential bright light on the horizon has been the introduction of murine models of antigen-induced bronchopulmonary eosinophilia in which the mechanisms of allergic airway disease can be explored [4—7]. The advantages of using mice for potential in vivo models of asthma are obvious; their extensive use in immunology research has provided us with a host of reagents with which to explore cellular and molecular mechanisms involved in the pathophysiology of airway disease, and the availabilty of transgenic and 'knock-out' mice for the multitude of adhesion molecules, cytokines and cells which have been implicated in asthma, will provide invaluable opportunities to study the mechanisms of allergic tissue inflammation. The identification in asthmatics of a subset of CD4 T cells exhibiting a profile of cytokine generation (interleukins-4, 5, 10 and 13) similar to that originally described for TH2 lymphocytes in mice [8] offers some reassurance that our animal models and clinical asthma may be moving onto common ground. Over the past 2-3 years there has been a marked increase in the number of publications appearing in the scientific literature which describe mouse models of allergic airway disease [4-7] in which mechanisms, thought to be relevant to asthma in man have been explored. The paper by Nagai et al., in this issue of Clinical and Experimental Allergy is one such example [9]. They describe a model of antigen challenge in sensitized mice, in which the presumably IL-5-dependent lung eosinophilia is divorced from antigen-induced changes in airway responsiveness. A similar claim has been made for a dissociation of airway responsiveness and bronchoalvoiar lavage cell composition in sensitized guinea-pigs [10]. Do we then make the tacit assumption that antigen-induced eosinophilia is an epi-phenomenon and that we should ignore the mountain of accumulated clinical evidence which demonstrates a link between the T cell-orchestrated influx of eosinophils into the airway wall and airway hyperreactivity in man, and in animal models including primates [11]?

Mouse models of allergic disease; how do they relate to asthma in man?

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Mouse models of allergic disease; how do they relate to asthma in man?