Kim DC, Hsu FI, Barrett NA, et al. J Immunol. 2006;176:4440–4448
PURPOSE OF THE STUDY. The cysteinyl leukotrienes (cysLTs), derived from the 5-lipoxygenase pathway, play an important role in asthma as smooth muscle constrictors of airways and microvasculature. This study investigated a potential additional role of cysLTs in T-helper 2 (Th2) cell-dependent pulmonary inflammation using an ovalbumin-sensitization and -challenge protocol with mice that lacked LTC4 synthase (LTC4S), the terminal pathway enzyme for cysLT biosynthesis.
METHODS. LTC4S-null mice and wild-type mice underwent intraperitoneal ovalbumin sensitization, followed on days 40, 43, and 46 by intranasal ovalbumin or saline challenge. Pulmonary histology was examined 48 hours after the last challenge. Total and ovalbumin-specific serum immunoglobulin (Ig) levels, cytokine mRNA expression in the lung, cytokine production by parabronchial lymph node cells after in vitro ovalbumin restimulation, delayed-type hypersensitivity, and airway hyperresponsiveness to methacholine 24 hours after the last challenge were measured also.
RESULTS. In the LTC4S-null mice, antigen-induced pulmonary inflammation (eosinophil infiltration and goblet and mast cell hyperplasia) and airway hyperresponsiveness to methacholine were significantly reduced. In addition, antigen-specific serum immunoglobulin E and G1 and Th2 cell cytokine messenger RNA expression in the lung were reduced in LTC4S-null mice compared with wild-type controls. The production of Th2 cytokines by antigen-restimulated parabronchial lymph node cells from LTC4S-null mice was also significantly reduced compared with those from wild-type controls; however, there was no suppression of cutaneous delayed-type hypersensitivity in LTC4S-null mice.
CONCLUSIONS. These findings support a role for cysLTs in the development and/or amplification of a pulmonary Th2 response.
REVIEWER COMMENTS. Two types of leukotriene-based medications have been used to treat patients with bronchial asthma: (1) leukotriene inhibitors that block the actual synthesis of leukotrienes and (2) leukotriene antagonists that inhibit leukotriene function by blocking leukotriene-receptor sites. Previous studies suggested that the main role of cysLTs was smooth muscle constriction of airways and microvasculature. This study, as well as other growing evidence, points to a unique and broader role for cysLTs in the initiation and amplification of the Th2 response in the lung. Future studies should assess the mechanism of this role, specifically the impact of cysLTs on dendritic-cell and T-cell function. Therefore, the therapeutic benefit of leukotriene antagonists may be additionally derived from this broader physiologic role of cysLTs in pulmonary Th2 responses.
- Copyright © 2007 by the American Academy of Pediatrics