Genetically manipulated mouse models of lung disease: potential and pitfalls

Abstract

Gene targeting in mice (transgenic and knockout) has provided investigators with an unparalleled armamentarium in recent decades to dissect the cellular and molecular basis of critical pathophysiological states. Fruitful information has been derived from studies using these genetically engineered mice with significant impact on our understanding, not only of specific biological processes spanning cell proliferation to cell death, but also of critical molecular events involved in the pathogenesis of human disease. This review will focus on the use of gene-targeted mice to study various models of lung disease including airways diseases such as asthma and chronic obstructive pulmonary disease, and parenchymal lung diseases including idiopathic pulmonary fibrosis, pulmonary hypertension, pneumonia, and acute lung injury. We will attempt to review the current technological approaches of generating gene-targeted mice and the enormous dataset derived from these studies, providing a template for lung investigators.

Pathogenesis of Idiopathic Pulmonary Fibrosis

“…We do so because there is no animal model that reliably recapitulates the pathologic changes in idiopathic pulmonary fibrosis (14, 15). The bleomycin model of lung injury is commonly used to study molecular pathways of pulmonary fibrosis.…”

Genetically Modified Animals in Pharmacology and Toxicology Research: Review

“…Örneğin; QT aralığı-nın uzaması sendromu gösteren hastalarda kullanı-lacak ilacın ileri kardiyovasküler testlerinin yapılması, astım modellerinde solunum güvenliği-nin test edilmesi, Alzheimerlı ve amitrofik lateral sklerozlu modellerde santral sinir sisteminin değerlendirilmesi için transgenik, knock-out, knockin ve spontan mutasyon modelleri geliştirilmiş ve başarıyla yürütülebilmiştir. 26,[49][50][51] GENETİĞİ DEĞİŞTİRİLMİŞ HAYVANLARIN GENOTOKSİSİTE ÇALIŞMALARINDA KULLANIMI Escherichia coli ile işaretlenmiş lacI, lacZ ve gpt deltayı kopyalayan birden çok genin yerleştirildiği transgenik rodentler, Avrupa'da ve ABD'de Çevre Koruma Örgütü tarafından kimyasal mutajenite testleri için kabul edilmektedir. Ancak, bunlar genellikle yalnızca ilave analizler olarak veya sadece mekanistik genotoksisite çalışmalarında kullanıl-maktadır.…”

The Immune Basis of Allergic Lung Disease

“…Mice can be sensitized to a wide array of allergens such as OVA, and HDM, Aspergillus fumigatus, ragweed, and cockroach antigens (Baron et al, 2012). Mouse models incorporating AHR, bronchopulmonary inflammation, and increases in IgE and mucus production have been described, and some chronic models have shown airway remodelingdall key features of human asthma.…”

“…Mucus metaplasia, accumulation of eosinophils in the airway, subepithelial fibrosis (Baron et al, 2012) IL-9 TG driven by CCSP Airway inflammation (eosinophils, lymphocytes), mast cell hyperplasia, bronchial hyperresponsiveness, subepithelial collagen deposition (Zhu et al, 1999) IL-4 TG driven by CCSP Mixed mononuclear and eosinophilic response, mucus metaplasia, mild fibrotic airway disease (Temann et al, 1998;McLane et al, 1998) IL-4 KO Lack of allergen-induced T H 2 cytokines, eosinophilia, Agspecific IgE, and AHR following sensitization and challenge. (Rankin et al, 1996) IL-5 TG driven by CCSP Tissue eosinophilia, mucus metaplasia, subepithelial fibrosis, AHR (Brusselle et al, 1995(Brusselle et al, , 1994Coyle et al, 1995b) IL-5 KO Lack of antigen-induced AHR and eosinophilia (Lee et al, 1997) IL-6 TG Lymphocytic infiltration in the airways and decline in AHR (Foster et al, 1996) IL-10 KO Decreased AHR, IL-5, eosinophilia, and mucus production.…”