Cyclooxygenase-2 expression during allergic inflammation in guinea-pig lungs

Prostaglandins and thromboxanes are important modulators of airway physiology. The synthesis of these mediators depends on two isoforms of cyclooxygenase (COX), constitutive COX-1 and inducible COX-2. COX-2 expression has been observed in various inflammatory diseases, but not all aspects of the expression and the role of COX-2 in conditions of allergic inflammation such as asthma are clear. In the present study, we examined the 72-h kinetics of the expression of COX-isoform mRNA in ovalbumin-sensitized and -challenged guinea-pig lungs. The sensitized animals showed a robust and transient induction of COX-2 mRNA expression within 1 h after ovalbumin challenge, whereas their COX-1 mRNA levels remained unchanged. Upregulation of the level and activity of COX-2 protein followed the induction of COX-2 mRNA. Lung slices harvested from ovalbumin-challenged animals released more prostaglandin D(2) and prostaglandin E(2) spontaneously or in response to A23187 (10 microM) ex vivo than did those from unchallenged animals. This response was significantly blocked by the COX-2 selective inhibitors, NS-398 and JTE-522. In vivo administration of NS-398 significantly inhibited the accumulation of eosinophils and neutrophils in the lungs. In conclusion, de novo COX-2 expression during allergic inflammation modifies prostanoid synthesis in the lung and airway pathophysiology.     

Inhalation challenge with sulfidopeptide leukotrienes in human subjects

What is the meaning of these findings to the practicing chest physician? First, leukotrienes are potent airway constrictors; they are capable of reproducing the type of airway constriction observed in asthma. The role of leukotrienes in this regard has yet to be established, but experiments to test the importance of these agents in this setting are likely to be performed soon. Specifically, several leukotriene receptor antagonists or synthesis inhibitors have been identified and may provide the tools needed to test this crucial hypothesis. Second, the leukotrienes are unique bronchoactive agents in that the degree of hyperresponsiveness between normal and asthmatic subjects varies markedly with the bronchoconstrictor index used to assess response. When one compares normal subjects to asthmatic subjects, there is substantial overlap in leukotriene sensitivity among groups when V30-P is used as the bronchoconstrictor index. However, when the FEV1 is used as the bronchoconstrictor index, there is little overlap in sensitivity between normal and asthmatic subjects, and the separation between the two groups is even more clearly made than it is with histamine or methacholine challenge. Thus, LTD4 inhalation challenge may replace the histamine and methacholine challenges in the diagnosis of cryptic shortness of breath. Third, the differential sensitivity of various bronchoconstrictor indices in both normal and asthmatic subjects when leukotrienes are used may provide clues as to the locus of airway hyperresponsiveness in asthma. Thus, leukotrienes hold the promise of new ways to treat and diagnose asthma, as well as providing new insights into the pathobiology of the disease itself.