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* From the Institute for Cardiovascular and Respiratory Pharmaceutical Development, University of Sunderland, Tyne & Wear, Sunderland, UK.
Correspondence to: Stephen Kilfeather, PhD, Institute for Cardiovascular and Respiratory Pharmaceutical Development, University of Sunderland, Tyne & Wear, Sunderland, SR1 3SD, United Kingdom; e-mail: SkilfeatherICRPD{at}aol.com
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Abstract |
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Key Words: antagonist • COPD • 5-lipoxygenase • 5-lipoxygenase inhibitor • leukotriene • leukotriene B4 • neutrophil
The rationale for targeting leukotrienes in the development of therapeutic agents for inflammatory disease is derived from their inflammatory cellular sources and activities. This thesis is endorsed by the capacity of leukotriene receptor antagonists and synthesis inhibitors to reduce certain inflammatory responses involving neutrophils when administered in vivo. The development of inhibitors of leukotrienes has evolved from the concept that these mediators are synthesized at the cell surface, and that their actions are mediated through cell surface receptors. It is now established that leukotriene production occurs at the nuclear membrane and that there are leukotriene receptors within different cellular compartments. There has been success in the development of inhibitors of leukotriene synthesis through the inhibition of 5-lipoxygenase (5-LO) and 5-LO activating protein (FLAP), and through antagonism of leukotriene B4 (LTB4) and cysteinyl leukotriene receptors (Fig 1 ). In the development of a therapy for the treatment of COPD, however, there may be an additional benefit derived from reduced specificity and the targeting of other aspects of arachidonic acid (AA) cascade such as through the inhibition of cyclooxygenase (COX).
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More recently, the potential involvement of the monocyte-macrophage cell lineage in the etiology of COPD and emphysema has received attention, including the potential for cells of this lineage as targets for leukotriene inhibition. The relatively low levels of neutrophils in the lower airways raises the possibility that neutrophilic inflammation in COPD patients could be more concentrated in the upper airways, while macrophage-derived mediators and proteases could provide a more predominant activity in the peripheral airways and alveolar region.
The investigation of the nuclear membrane site of 5-LO activity and the existence of differing cell surface receptors and nuclear receptors could extend the future avenues for exploration of leukotriene inhibition. The inhibition of noncysteinyl leukotrienes such as LTB4 will not provide a route for bronchodilatation. The success of treatment with compounds under development in antileukotriene and other anti-inflammatory cell classes in COPD patients depends, therefore, on the capacity of early-stage clinical studies to test the "proof of concept" in efficacy through the examination of surrogate markers of airway inflammation or lung function.
The impetus for the exploration of leukotrienes, particularly LTB4 in COPD patients, is derived from the consistent level of sputum neutrophilia in patients with this condition. The levels of neutrophilia have a wide range among patients (ie, < 5% to > 90%) and this range has supported the consensus view that neutrophils provide a significant contribution to the development of chronic inflammation and airway remodeling in COPD. The presence of neutrophilia is not consistent in BAL fluid or in the lower airway wall, and this raises the possibility that neutrophil-mediated inflammation could be more significant to the etiology of the symptomatic features of COPD that are observed in the upper airways. The macrophage provides an alternative candidate cell as the main promoter of inflammation in the lower airways and alveolar regions in COPD patients, and has received more attention recently as a potential target for development of agents to modulate the inflammatory and structural changes in COPD. Macrophages are also a source of LTB4, and their behavior is influenced by leukotrienes. As discussed below, LTB4 appears to be involved in macrophage phagocytosis of Klebsiella. Agents that inhibit leukotriene activity, therefore, may reduce macrophage activities throughout the airways and may reduce the effects on neutrophil activation and migration.
The capacity for leukotrienes, particularly LTB4, to amplify neutrophil activity1 has supported the drive to develop compounds with an anti-inflammatory activity that is mediated through the inhibition of leukotrienes and thereby undermines neutrophil activity in inflammatory conditions. The potential efficacy of LTB4 antagonists against neutrophilic aspects of airway inflammation in humans has been observed through reductions in the number of airway neutrophils following antigen challenge in asthmatic patients2 (Table 1 ). Currently, there are long-acting and potent LTB4 receptor antagonists that have shown efficacy against inflammation and neutrophilia in primates.3 This class of compound has also shown efficacy in models of other inflammatory conditions, including arthritis.4 Members of the 5-LO inhibitor, FLAP inhibitor, and dual 5-LO/COX inhibitor classes, together with LTB4 receptor antagonists have all demonstrated the inhibition of neutrophil influx and tissue edema when administered orally to animals. In the case of the synthesis inhibitors, this often has been associated with a reduction in tissue LTB4 levels and LTB4 synthesis ex vivo from circulating neutrophils.
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.9
This receptor is related to the PPAR-
receptor, which is a receptor to 15-deoxy-
12,14-prostaglandin J2, a metabolite of prostaglandin D2.10
In isolated cell studies, agonists of these receptors exert effects that are similar to those of corticosteroids, resulting in the reduction of levels of interleukin (IL)-2, IL-6, IL-8, tumor necrosis factor-, and matrix metalloproteinases. This has led to the concept that cellular physiologic responses to LTB4 could represent an integration of proinflammatory and anti-inflammatory actions that are mediated by the cell surface receptors and nuclear receptors, respectively (Fig 2)
. In this context, compounds that interact with both cell surface and nuclear receptors have been developed, displaying differential agonist and antagonist properties at each receptor subtype11
(Table 2
). It is noteworthy, however, that agonists to PPAR- and PPAR-, when administered in vivo, have been found to cause the elevation of circulating tumor necrosis factor- levels, implying further complexity to the potential regulation of leukotriene involvement in inflammation when targeting PPAR receptors.
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A potential problem in the development of a class of compounds aimed at reducing neutrophilic inflammation is the reduction of neutrophil-dependent host defense. Corticosteroid agents are used to accelerate the resolution of inflammation during exacerbations of COPD. This apparent reassurance for the use of anti-inflammatory compounds in treating COPD patients should be viewed with the awareness that neutrophilia can result from oral corticosteroid administration and that corticosteroids promote neutrophil survival.12 Therefore, while corticosteroids have been found to reduce neutrophil accumulation under certain conditions, they may potentially elevate certain aspects of neutrophil defense. LTB4 contributes to neutrophil survival and BLTR antagonism reverses neutrophil survival responses.6 LTB4 receptor antagonism could, therefore, target aspects of neutrophilic inflammation that are insensitive to corticosteroids, and the combined effect of corticosteroid and LTB4 inhibitor on host defense has not been fully explored.
Several studies have been conducted in 5-LO knockout mice to test their response to a range of infections and to sensitization to ovalbumin.13 Overall, the mice showed reduced neutrophil responses to infection, but survival was not impaired to a significant degree, apart from infections involving Klebsiella pneumoniae.14 Further studies revealed that macrophages from genetically 5-LO-deficient mice show impaired phagocytosis of K pneumoniae, which can be restored by the addition of LTB4.15 This may imply caution under certain circumstances in the use of 5-LO inhibitors.
5-LO knockout mice also showed reduced responses following attempts to sensitize them to ovalbumin, and we have observed a reduction in the capacity to sensitize mice to ovalbumin when treating them during the sensitization period with FLAP inhibition or cysteinyl leukotriene receptor antagonists. These findings are consistent with the influence of 5-LO products over the development of certain immune responses. In the context of COPD, several reports appeared a decade ago concerning the capacity for LTB4 to influence lymphocyte differentiation, and the findings demonstrated consistently an up-regulation of the CD8 suppressor lymphocyte phenotype. This may be of relevance to the cause of increased numbers of CD8+ cells that are observed in the airways of COPD patients, but a direct link between elevated LTB4 levels and their involvement in the up-regulation of CD8 cells in COPD patients would be difficult to establish.
It appears that the inhibition of 5-LO will exert effects on both immune and inflammatory responses in COPD patients, and this may be of benefit in reducing the acute inflammatory responses, in which those responses are excessive, even if the progression of the disease is not slowed. An examination of the capacity of these classes of compounds to influence exacerbation frequency, duration, or intensity in COPD patients is required to generate confidence that the inhibition of leukotrienes will undermine excessive rather than crucial defenses.
There are potentially unseen hurdles to the development of leukotriene inhibitors as anti-inflammatory agents in COPD patients. For example, certain 5-LO inhibitors appear to require glutathione for optimal activity, and this raises the potential for a loss of potency of this class of agents in treating COPD patients, in whom glutathione levels are compromised under conditions of oxidative stress that are likely to be encountered in cells in COPD patients.
One of the largest obstacles to the successful development of classes of anti-inflammatory compounds that have no bronchodilator action and none of the profound immunomodulatory effects of corticosteroids is the difficulty in generating studies that will adequately test drug efficacy. In COPD treatment, the clinical development of such classes of compounds is dependant on the requirement to see an early sign of proof of concept before engaging in more protracted trials. A proof-of-concept study often will involve an examination of effects on a surrogate marker that is not guaranteed to produce a quick readout, such as effects on neutrophilia or neutrophil activation. It is noteworthy that the reductions in airway neutrophils observed by Evans et al2 due to LY293111, a BLTR antagonist, following antigen challenge in asthmatic patients were significant but were achieved from a very low pretreatment baseline compared with the level of sputum neutrophilia observed in COPD patients. In addition, the correct mode of assessment of indexes of neutrophil activity has not been confirmed. Figure 3 illustrates in a group of patients with COPD the diminishing effect of changes in absolute sputum cell number on the proportion of cell population occupied by neutrophils in sputum at high neutrophil concentrations. The implication from this observation is that treatment-induced reductions in cell content from high pretreatment baseline levels (ie, > 70% neutrophilia) may not be observed if only percentages of neutrophils are measured. The measurement of absolute cell numbers in the examination of effects of leukotriene inhibition or other anti-inflammatory strategies on neutrophilia may be more difficult to measure accurately compared to the measurement of neutrophils as a percentage of total cell population, but may be necessary to see efficacy.
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In conclusion, the complexity of leukotriene regulation of cell behavior and, therefore, the scope for the redesign of 5-LO inhibitors and leukotriene receptor antagonists will make for a further evolution of this route of anti-inflammatory development. The main hurdles to the future establishment of these compounds in the treatment of COPD appear to be the potential for undermining crucial aspects of host defense responses and the capacity to adequately test the efficacy of the compounds in early clinical development stages.
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Footnotes |
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References |
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TOPAbstractReferences |
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-leukotriene B4 pathway to inflammation control. Nature 384,39-43[CrossRef][Medline]
and BLTR, nuclear and cell surface receptors for leukotriene B4. J Biol Chem 274,23341-23348This article has been cited by other articles:
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  G. Riccioni, C. Di Ilio, P. Conti, T. C. Theoharides, and N. D'Orazio Advances in Therapy with Antileukotriene Drugs Ann. Clin. Lab. Sci., October 1, 2004; 34(4): 379 - 387. [Abstract] [Full Text] [PDF]
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