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properties and the therapy has been shown to have an acute and sustained beneficial effect on lung function (changes in FEV 1 ) in chronic persistent asthma [6] . Antileukotrienes do not have major side effects and appear to be well tolerated by most patients [7] , but a limitation of their widespread use may be due to the large percentage of nonresponders [8] . However, for those intolerant or resistant to corticosteroids but responsive to antileukotrienes, treatment with leukotriene inhibitors has become an invaluable therapeutic option. There are two types of leukotriene inhibitors: the leukotriene receptor antagonists such as montelukast and those that inhibit leukotriene formation such as zileuton. Zileuton is an inhibitor of the enzyme 5-lipoxygenase, which forms leukotrienes from arachidonic acid. The network of signaling pathways associated with leukotrienes is complex and is not completely understood [6] . The findings by Chen et al. [2] have shed light on this subject, specifically with regard to perturbations in the signaling pathways seen in allergen-sensitized animals. They have identified some potentially important downstream molecular players in leukotriene signaling in ovalbumin-sensitized rats with chronic inflammation, thickened airway walls and reduced lung function. They also showed that zileuton significantly reduced the expression of biomarkers of chronic inflammation, significantly reversed the airway remodeling and improved lung function in these sensitized, bronchohyperresponsive rats. A thickened airway wall with increased airway smooth muscle mass and extracellular matrix deposition as a result of airway remodeling is a hallmark of persistent asthma. The mechanism underlying the remodeling process is not entirely clear. It is thought that the chronic airway inflammation seen in asthma is a major contributor, but anti-inflammatory strategies often do not bring resolution to airway remodeling [1] . Findings reported by Chen et al. [2] in this issue of Respiration explore the effects of the leukotriene inhibitor (zileuton) on airway remodeling in an ovalbumin-sensitized rat model and revealed that downstream pathways of leukotriene stimulation contribute to airway remodeling. Furthermore, the leukotriene signaling appears to follow the same pathways as those considered to be linked to tumorigenesis [3, 4] . These findings suggest a common mechanism underlying the increase in airway tissue mass seen in chronic asthma and the tumor growth seen in malignancy. The primary components of asthma treatment separately target acute airway obstruction and chronic airway inflammation. Bronchodilators (predominately β 2 agonists) are used to treat the acute symptoms and corticosteroids are used to control inflammation. Increasingly, antileukotriene agents are being added to inhaled corticosteroids in combination therapy, especially for severe asthma. Antileukotrienes are also used on their own as a frontline therapy, mostly for mild asthma [5] . Antileukotrienes have both anti-inflammatory and bronchodilatory Published online: August 29, 2013

inducing a proteolytic burden in the lung microenvironment. Under normal circumstances, A1AT and other antiproteases neutralize this threat posed by neutrophils. However, in A1AT deficiency, defenses are perturbed, leading to elastic degradation on lung tissue resulting in emphysema. While most COPD patients do not have A1AT, this genetic syndrome serves as a useful human model of how disturbances in the protease-antiprotease system can lead to emphysema. Since most patients with COPD have adequate circulating levels of A1AT, according to this theory, aberrant neutrophil activity is at the heart of COPD pathogenesis and by turning off excess neutrophil recruitment and activation (e.g. through smoking cessation) COPD progression can be halted. However, even with smoking cessation, the inflammatory process in the lungs persists once COPD becomes firmly established and in many patients the disease continues to progress [5] . The reason for these observations is obscure. In this issue of Respiration, Milara et al. [6] offer new insights into the role of neutrophils in COPD that may in part explain the conundrum of disease progression in COPD in ex-smokers. The authors studied subjects with severe COPD developed at an early age ( ! 56 years) and showed that, despite years of smoking cessation, the neuChronic obstructive pulmonary disease (COPD) is a menace affecting 300 million people worldwide and is responsible for 3 million deaths annually [1] . Despite this, its pathophysiology is not well understood. It is now well accepted that lung inflammation exists in COPD and that the inflammatory process intensifies with disease progression [2] . The most important environmental risk factor in COPD is cigarette smoking; it is responsible for more than 50% of the cases worldwide. Interestingly, although all smokers eventually develop lung inflammation, only about 15–20% of smokers incur COPD [3] . On the other hand, nearly 100% of smokers with rare genetic mutations in the SERPINA1 gene located in the long arm of chromosome 14 develop lung inflammation and COPD in their 40s and 50s [4] . Nearly 100% of all individuals with the null-null allele in this gene, which encodes for alpha-1-antitrypsin (A1AT) (resulting in undetectable serum A1AT concentrations), develop COPD and 80–100% of those with the S-Z allele (resulting in serum A1AT concentrations of 2.5–7 mmol/l) develop COPD [4] . Why are individuals with A1AT deficiency so susceptible to COPD? It is postulated that with cigarette smoking neutrophils and other inflammatory cells are recruited to the lungs. When activated, neutrophils release proteolytic enzymes such as elastase and other proteolytic enzymes, Published online: December 6, 2011