Interleukin-13 and leukotrienes: an intersection of pathogenetic schema.

The episodic wheezing and shortness of breath caused by events in asthma, have not been extensively investigated. In this issue of the AJRCMB, Vargaftig and Singer address asthma has been recognized since antiquity. As a result, major efforts have been directed at studies of asthma pathothis gap in our knowledge and demonstrate, for the first time, that LTs play a critical role in IL-13 effector pathway genesis. In the modern scientific era, these studies have caused an impressive evolution in our understanding of the proactivation (1). To put these observations into perspective, the importance of Th2 inflammation and IL-13, the mechacesses that contribute to this disorder. A number of years ago, the airways dysfunction in asthma was viewed largely nisms of IL-13 phenotype generation, and the role of LT in asthma are reviewed below. from the perspective of airways smooth muscle contraction (bronchospasm). It was assumed that an intrinsic abnormality in airway myocyte contractility was the cornerstone of Th2 Cells and IL-13 in Asthma the asthmatic diathesis. This was followed by the contention A major advance in our understanding of the immunopathothat asthma is a disease characterized by autonomic dysgenesis of chronic inflammatory disorders such as asthma function with cholinergic and/or tachykinin excess, and then occurred when it was appreciated that the type of response by the appreciation that IgE-mediated mast cell and/or bathat is generated by an antigen is influenced greatly by the sophil degranulation is a key event in the acute asthmatic types of T cells that accumulate at the site of local antigen response. Relatively recently studies using bronchoalveolar deposition. This was most clearly demonstrated in the lavage (BAL) and bronchial biopsy demonstrated promimouse, where a number of functionally distinct CD4 T cells nent eosinophil-, macrophage-, and lymphocyte-rich inflamhave been defined based on the profile of the cytokines mation in asthmatic airways. When coupled with the well they elaborate. Th1 and Th2 cells have been the topic of the established clinical efficacy of steroids and the repeated most intense study, with the former elaborating interferon demonstration of airway remodeling in the asthmatic air(IFN), IL-2, and lymphotoxin, and the latter elaborating way, these findings led to the present-day concept that asthma IL-4, IL-5, IL-9, IL-13, and IL-10. Th1-polarized responses is a chronic inflammatory disorder of the airway in which play a key role in macrophage activation and delayed-type T helper (Th)2 cytokines such as interleukin (IL)-13 are hypersensitivity reactions. In contrast, Th2-dominant repivotal effectors of inflammation and remodeling events sponses stimulate antibody-mediated responses, activate that contribute to disease pathogenesis. Simultaneously, scimast cells, elicit IgE production, and induce tissue eosinoentists discovered and characterized the leukotriene (LT) philia. Th1-dominated responses are seen in a variety of products of arachidonic acid (AA) metabolism and develdiseases, including sarcoidosis and tuberculosis. In contrast, oped a variety of LT antagonists that were shown to be studies of biopsies and BAL from individuals with asthma effective asthma therapeutics. This led to the widely held have most often demonstrated enhanced production of Th2 belief that LTs are also critical mediators in asthma pathocytokines including IL-4, IL-5, and IL-13 (2–4). In keeping genesis. Surprisingly, however, the relationships between with the importance of IgE and eosinophils, asthma is now the cytokines that are central to the Th2 inflammation hylooked at as a disease that is characterized by Th2 cell and pothesis, and the LT that are central to the lipid regulatory Th2 cytokine excess (4, 5). The appreciation that Th2 inflammation is the likely cornerstone of asthma pathogenesis quickly led to studies (Received in original form January 28, 2003) that were designed to define the contribution(s) of individAddress correspondence to: Jack A. Elias, M.D., Section of Pulmonary and ual Th2 cytokines in this disorder. These studies demonCritical Care Medicine, Yale University School of Medicine, Department strated that IL-4 plays an important role in the early initiaof Internal Medicine, 333 Cedar Street, 105 LCI, New Haven, CT 06520tion phases of Th2 inflammation. Surprisingly, in the setting 8057. E-mail: jack.elias@yale.edu of established disease, IL-4 was not obligatory for the generAbbreviations: 5-lipoxygenase, 5-LO; arachidonic acid, AA; airway hyperation of the asthmatic phenotype (6, 7). In contrast, multiple responsiveness, AHR; bronchoalveolar lavage, BAL; epidermal growth factor receptor, EGFR; interferon, IFN; immunoglobulin E, IgE; leukolines of experimental evidence have demonstrated that triene, LT; matrix metalloproteinase, MMP; transforming growth factor, IL-13 is a critical effector that is both necessary and, in some TGF; T helper, Th. cases, sufficient for the allergic response. This includes studAm. J. Respir. Cell Mol. Biol. Vol. 28, pp. 401–404, 2003 ies that demonstrated that IL-13 blockade reverses airways DOI: 10.1165/rcmb.F264