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Review
. 2003 Feb;111(3):291-7.
doi: 10.1172/JCI17748.

New insights into the pathogenesis of asthma

Jack A Elias  1 , Chun Geun Lee, Tao Zheng, Bing Ma, Robert J Homer, Zhou Zhu
Affiliations
Review

New insights into the pathogenesis of asthma

Jack A Elias et al. J Clin Invest. 2003 Feb.
No abstract available

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Figures

Figure 1
Figure 1
Inflammation and remodeling in the asthmatic airway. There is impressive inflammation (I), mucus plugging (MP), subepithelial fibrosis (SF), myocyte hypertrophy and hyperplasia (MH), and neovascularization (N) in this autopsy lung section from a teenage asthmatic individual.
Figure 2
Figure 2
Development of Th1 and Th2 lymphocytes. Antigens enter through the endobronchial tree, cross the epithelial surface, and interact with naive Th cells and DCs. As a result of signals from the surrounding microenvironment, they differentiate into Th1 cells, which produce IFN-γ, IL-2, and lymphotoxin (LT), or Th2 cells, which produce IL-4, IL-5, IL-9, IL-13, and IL-10. Polarization into Th1 cells occurs via a STAT-1– and T-bet–dependent pathway under the influence of CD8α+ DCs and macrophage-derived cytokines such as IFN-γ, IL-12, and IL-18. Differentiation into Th2 cells occurs via a pathway that involves STAT-6, GATA-3, nuclear factor of activated T cells-c (NFATc), and c-maf under the influence of CD8α– DCs and IL-4, which may come from mast cells.
Figure 3
Figure 3
Generation of transgenic mice. To express a transgene in vivo, the investigator first makes a construct containing the transgene being evaluated. A typical construct is illustrated in a. It contains a promoter that targets the transgene to the desired organ, the transgene being expressed, and intronic and polyadenylation sequences that ensure the proper processing of the mRNA transcripts that are produced. The methodology for generating transgenic mice is illustrated in b. Fertilized eggs are washed out of the oviducts of female mice. They are then microinjected under direct visualization and implanted into the uterus of pseudopregnant female mice. The genotype of the pups that are produced is evaluated in tail biopsy–derived DNA using PCR reactions or Southern blot evaluations.
Figure 4
Figure 4
Demonstration of the effects of transgenic IL-13 on airway fibrosis and mucus metaplasia. (a) Trichrome stains are used to compare the amount of blue-staining collagen around airways from transgene-negative mice (left) and transgene-positive mice (right). (b) Alcian blue stains are used to demonstrate mucus accumulation in airways from transgene-negative mice (left) and transgene-positive mice (right). Mucus is blue in this evaluation.
Figure 5
Figure 5
Use of null mutant (knockout) mice to define the pathways that transgenes use to generate disease-relevant phenotypes. In these experiments, transgenic mice with a disease-relevant phenotype (for example, fibrosis or inflammation) are mated with mice that have a null mutation of a downstream gene that is believed to play an important role in the generation of this phenotype. Transgene-positive (TG[+]) and transgene-negative (TG[–]) mice are generated that have normal downstream genes (+/+), are heterozygote knockout at the downstream gene in question (+/–), or are null-mutant for the downstream gene in question (–/–). The presence and intensity of the phenotypes of these mice are then compared. These comparisons allow an investigator to define the role(s) that this downstream gene plays in the generation of the pathologic response.
Figure 6
Figure 6
Mechanisms of IL-13–induced phenotype generation. IL-13 binds to the IL-13 receptor complex made up of IL-4 receptor α (IL-4Rα) and IL-13 receptor α1 (IL-13Rα1). IL-13 also binds to IL-13Rα2, which is a decoy receptor that inhibits IL-13 responses. After binding to the IL-13 receptor complex, IL-13 activates STAT-6 signal transduction pathways. Pathways that involve chemokines, the chemokine receptor CCR2, MMPs, urinary plasminogen activator (UPA), TGF-β1, VEGF, and/or adenosine are then activated, and inflammation, fibrosis, blood vessel alterations, and mucus responses are generated. Each of these pathways is a site against which therapeutic agents can be directed.
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