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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 1-4, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.F251

Perspective

Of Mice and Men

William M. Abraham

Division of Pulmonary and Critical Care Medicine, University of Miami School of Medicine at Mount Sinai Medical Center, Miami Beach, Florida

Address correspondence to: William M. Abraham, Ph.D., Department of Research, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140. E-mail: abraham{at}msmc.com

Abbreviations: 5-lipoxygenase, 5-LO • airway hyperresponsiveness, AHR • bronchoalveolar lavage fluid, BALF • cysteinyl leukotriene, CysLT • interleukin, IL • leukotriene, LT

When arachidonic acid is released from cellular phospholipids by the action of phospholipase A2, it can be oxidatively metabolized by 5-lipoxygenase (5-LO) to form leukotrienes. In the presence of active 5-LO, arachidonic acid is first converted to the unstable intermediate 5-hydroperoxyeicosatetraenoic acid, and then to the unstable epoxide leukotriene (LT)A4. LTA4 is then converted either to LTB4, via LTA4 hydrolase, or to LTC4 by LTC4 synthase. Once formed LTC4 is actively transported extracellularly, it is metabolized to LTD4 by removal of glutamic acid by {gamma}-glutamyl transpeptidase, and then to LTE4 by the removal of glycine by the action of extracellular dipeptidases. Lung cells that are fully capable of de novo synthesis of these cysteinyl leukotrienes (CysLTs, i.e., LTC4, LTD4, and LTE4), and that are involved in asthma pathophysiology, include mast cells, basophils, eosinophils, and macrophages (1).

The biologic actions of LTB4 and the CysLTs differ. LTB4 is considered a proinflammatory mediator that primarily acts as a potent neutrophil chemotaxin (2, 3), whereas the CysLTs are potent bronchoconstrictors (4–6), increase vascular permeability (7, 8), cause mucus secretion (9, 10) and mucociliary dysfunction (11), stimulate eosinophil recruitment (12–14), and can increase nonspecific bronchial responsiveness (15). Many of the actions of the CysLTs parallel clinical features seen in patients with asthma, and with the increased concentrations of CysLTs in bronchoalveolar lavage fluid (BALF) (16, 17), plasma (18), and urine (19, 20) of patients with asthma after antigen challenge in the laboratory or after acute exacerbations, supports the importance of these mediators in the pathogenesis of asthma. In the human lung, CysLTs exert their action primarily through the CysLT1 receptor (21). The CysLT1 receptor is a G-protein–coupled transmembrane receptor found on airway smooth muscle cells and a number of inflammatory cells, including eosinophils, basophils, pregranulocytic CD34+ cells, monocytes, and B lymphocytes (21). A CysLT2 receptor has also been identified (22); however, for the purposes of this discussion, the receptor of interest is the CysLT1 receptor.

Successful protection against the bronchoconstictor effects in acute challenge models (i.e., cold air, exercise, and allergen), followed by longer-term clinical trials in patients with asthma, led to the introduction of CysLT1 receptor antagonists (MK-0476, montelukast; Singulair [Merck, West Point, PA]; ICI-204219, zafirlukast; Accolate [AstraZeneca, Wilmington, DE]; ONO-1078, pranlukast [ONO/SmithKline Beecham, Pittsburgh, PA]) for the treatment of asthma (1, 23–25). Clinically, these CysLT1 antagonists improve lung function and reduce asthma exacerbations (23, 25). They have been shown to be effective agents when combined with inhaled corticosteroids (26, 27), and have a steroid-sparing effect (28). Although there is little argument that these antagonists can protect against the spasmogenic effects of the CysLTs, the evidence is more controversial concerning the anti-inflammatory properties of these agents. This anti-inflammatory designation becomes important because asthma is now classified as an inflammatory disease of the airways. Thus, even though the CysLT1 antagonists have been shown to be beneficial in controlling asthma, it is still unclear as to whether this control is, in part, related to the putative anti-inflammatory actions of these compounds.

Allergen challenge studies in patients indicate that the acute inflammatory component of asthma is characterized primarily by the recruitment of eosinophils and by the influx of activated Type 2 helper (Th2) CD4+ T-lymphocytes (29–33). It is well established that allergen challenge increases the levels of Th2 cytokines including, but not limited to, interleukin (IL)-4, IL-5, and IL-13 in BALF and increases mRNA expression of these cytokines in airway cells (34–36). In this setting, IL-5 and the chemokine eotaxin appear to play pivotal roles in eosinophil recruitment, survival, and activation (37), an important finding given the myriad of preclinical and clinical studies that implicate eosinophils and Th2 lymphocytes with the development of allergen-induced airway hyperresponsiveness (AHR) (32, 33, 38, 39). Thus, strategies to prevent the recruitment and/or activation of eosinophils have been pursued extensively in the hopes that allergen-induced eosinophilic inflammation, and therefore the allergen-induced AHR, can be controlled. These strategies include, but are not limited to: inhibition of the integrin {alpha}4B1 (40, 41), an eosinophil cell surface adhesion molecule critical to migration through the vascular endothelium and adherence to matrix tissue; antagonism of IL-5 (42), and antagonism of the CCR-3 receptor (43), which is the exclusive ligand of eotaxin.

Whether the CysLTs contribute to this eosinophilic inflammation, and whether there is an anti-inflammatory role of CysLT1 antagonists in this regard, is controversial. LTD4 is a chemoattractant for eosinophils in vitro (44), and in guinea pigs inhaled LTD4 induced BALF eosinophilia, a response that was blocked by the CysLT1 receptor antagonist pranlukast (45). This LTD4-induced eosinophilia could also be blocked by an antibody to IL-5, suggesting a potential interaction between these mediators (45). Such a result would be consistent with data showing colocalization of the CCR-3 receptor with the CysLT1 receptor on eosinophils (21), and would support reports of increased eosinophil recruitment to the airways of patients after inhalation of LTD4 (12) or LTE4 (46). Others, however, have not validated the latter findings (47). Likewise, inconsistent results have been obtained in studies where CysLT1 receptor antagonists were used to block allergic inflammation (48, 49).

Animal models of allergic inflammation have been informative in attempting to dissect the pathways involved in the recruitment of eosinophils to the airways and the resulting functional consequences of such recruitment. The use of murine models of asthma has increased dramatically because of the immunologic tools available to block specific pathways and the ability to selectively knockout genes that are important for processes that contribute to the pathogenesis of the disease. Controversy does exist, however, as to the relevance of these murine models of asthma (50, 51).

Although differences in strains and sensitization protocols can affect the antigen-induced responses, allergen challenge in sensitized animals leads to accumulation of eosinophils, Th2 lymphocytes, and their associated cytokines in the lung, and this inflammatory response is accompanied by an increase in AHR (52–54). Different experimental paradigms have dissociated these events such that allergen has induced airway eosinophilia but not AHR (55), and vice versa AHR without eosinophil influx (55). A review of the literature examining the pathogenesis of airway eosinophilic inflammation and AHR in mouse models indicates that three distinct pathways lead to the development of AHR: one dependent on immunoglobulin E and mast cells, one dependent on eosinophils and IL-5, and the third dependent on IL-13 (56). Therefore, agents that potentially disrupt one of these three pathways could block AHR, but this may not necessarily involve the eosinophil response.

In this issue of the AJRCMB, Eum and coworkers use a murine model to assess the role of CysLTs in allergen-induced airway eosinophilia and AHR (57). They show that these allergen-induced endpoints are blocked by montelukast, but that the effects do not appear to be mediated through the IL-5/eotaxin axis. They also show that although LTD4 challenge does not elicit either eosinophilia or AHR, in combination with allergen the AHR response is enhanced. There is, however, a difference in the cellular response, depending on whether the LTD4 is given before or after the antigen.

That montelukast blocks the allergen-induced eosinophilia is consistent with other studies in murine models using 5-LO inhibitors (58), 5-LO knockouts (59), or montelukast (60, 61) itself. In most, but not all of these studies (61), the inhibition of the eosinophil response was linked to blockade of the associated AHR. Nevertheless, as the authors point out, the protection they observed against the AHR with montelukast in this acute antigen challenge paradigm is consistent with results obtained in other animal models of asthma (36, 62, 63) and more importantly in patients (49).

How does montelukast reduce the eosinophilia without inducing a concomitant change in the IL-5/eotaxin axis? Missing changes in eotaxin may have been related to the sampling time relative to the allergen challenge. Kinetics of eotaxin production in sensitized guinea pigs after antigen challenge indicated that peak eotaxin levels occurred at 6 h after challenge (64, 65), which is consistent with the increases seen in patients 4 h after segmental allergen challenge (66). In the guinea pig study, the largest increase in BALF eosinophils occurred 12–24 h after challenge (64). These findings suggest that eotaxin plays a significant role in early eosinophil accumulation in the lung, but that other cytokines or mediators are involved in the later stages of recruitment. Thus, in the present study, if there were differences in eotaxin levels between treated and nontreated animals, these differences may have been missed because measurements of eotaxin levels at 24–48 h after challenge may have occurred too late.

Likewise, montelukast, at a dose that resulted in a reduction in eosinophils and protection against the AHR, did not significantly affect IL-5 levels. Furthermore, changes in IL-5 levels did not reflect the enhanced eosinophilia seen when LTD4 was given before antigen. Although this data supports the argument that the CysLTs may not mediate their effects on eosinophils through IL-5 (or eotaxin), one could also argue that reliance on these surrogate markers may not be as predictive and perhaps informative as the normalization of airway function. Such a conclusion is supported by the results of the initial clinical trials with anti–IL-5 antibodies (42).

The third and possibly most interesting findings are related to the experiments where LTD4 was added before or after allergen challenge. In both instances, the AHR was greater than that seen with allergen alone; however, the cell response as recovered from the BALF was different in the three trials. These differences were apparent in spite of the fact that IL-5 levels were comparable in all trials. The biggest difference in the cell profile in the LTD4 addition experiments was the increase in neutrophil numbers, with the largest increase associated with the most severe AHR. Is this an important observation signaling the activation of additional pathways that contribute to the development of AHR, or merely another surrogate marker that, in the end, has little relevance to the inflammation of asthma? Perhaps, as has been suggested for human asthma, the appearance of the neutrophil indicates a more severe inflammatory response (67–69).

If the protection afforded by montelukast against the eosinophilic inflammation and AHR were not mediated through IL-5 and/or eotaxin, then which pathways were involved? There are reports that in guinea pigs inhaled murine IL-13 induces hyperresponsiveness to histamine, and that this is associated with BALF neutrophilia and eosinophilia (70). IL-13 and IL-4 have been reported to upregulate CysLT1 receptor expression on human monocytes and macrophages (71). These studies would suggest that IL-4 and IL-13 levels be examined after montelukast treatment in challenged animals. This in fact has been done in a more chronic murine model of allergic inflammation (61). In these studies, montelukast significantly reduced multiple indices of airway inflammation and remodeling. Compared with the untreated challenged animals, this protection included reductions in: airway eosinophil infiltration, mucus plugging, smooth muscle hyperplasia, IL-4 and IL-13 mRNA expression in lung tissue, and their levels in BALF. Despite these changes, montelukast failed to alter the AHR in these animals (61). On one hand, it is somewhat puzzling that normalization of airway function was not achieved in the face of this anti-inflammatory profile. On the other hand, these results confirm the fact that it is difficult to delineate all the factors involved in the development of AHR (Figure 1).



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  		Figure 1. Summary of the reported clinical responses to CysLT1 receptor antagonists and experimental observations using CysLT1 receptor antagonists in acute and "chronic" allergen challenge models. The experimental pathways depicted are not intended to be inclusive, but are relevant to this discussion. Clinically, functional protection afforded by the CysLT1 receptor antagonists may or may not be associated with a reduction in surrogate inflammatory markers. In the acute allergic inflammatory models (both in patients and animal models), CysLT1 receptor antagonists block the functional endpoints listed, including allergen-induced airway hyperresponsiveness, but again this may or may not correlate with inflammatory markers. In the chronic models, CysLT1 receptor antagonists block the inflammatory endpoints, including cytokine and cell recruitment, but fail to block the airway hyperresponsiveness associated with more prolonged antigen exposure. Additional studies will be needed to explain this dichotomy between changes in structure (inflammatory changes leading to airway remodeling) and function (airway hyperresponsiveness). APC, antigen-presenting cell; (-), inhibition; (+), stimulation.

 
So, are the CysLT1 receptor antagonists anti-inflammatory or not?

Received in original form October 22, 2002


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