Both bronchial asthma and chronic obstructive pulmonary disease (COPD) are defined as inflammatory diseases in recent worldwide guidelines,1, 2 although the inflammatory process for each disease is different. In this review, I describe some differences in the inflammatory processes in each disease.

Bronchial asthma is characterized as chronic airway inflammation from the central to the peripheral airways involving various cell types such as activated mast cells/eosinophils and T helper 2 lymphocytes (Th2), which release mediators that contribute to asthma symptoms (Table 1).1, 3-10 Actually, many cytokines and growth factors such as IL-4, IL-5, and GM-CSF can be monitored with exhaled breath condensate (EBC) (Table 2).11 Clinically, examination of the eosinophil infiltration into the airways (sputum) is useful for discriminating asthma from COPD.12, 13

On the other hand, in COPD, the inflammatory cells that infiltrate into the airways/lung are different (Fig. 1).13 Macrophages are increased in the lungs of patients with asthma and COPD, however, they are more increased in COPD than in asthma. These macrophages are derived from circulating monocytes, which migrate to the lungs in response to chemoattractants such as CC-chemokine ligand 2 (CCL2), also known as MCP1, acting on CCR2, and CXCL1 acting on CXCR2.14

Neutrophils are also increased in the sputum of patients with COPD and are correlated with the disease severity.15

However, during exacerbations in both diseases, inflammatory cell infiltration into the airways becomes less selective, that is, there is neutrophil infiltration in asthma and eosinophil accumulation in COPD, possibly due to virus-induced chemokine production via the epithelium.

In asthma, cysteinyl leukotrienes are potent bronchoconstrictors and proinflammatory mediators mainly derived from mast cells and eosinophils. They are the only mediator whose inhibition has been associated with an improvement in lung function and asthma symptoms.1, 16 Histamine and prostaglandins are also released from mainly mast cells and contribute to the bronchomotor tone in asthma.1 Therefore, functional antagonists, such as β2-stimulants, cause more potent bronchodilation than anti-cholinergic agents in bronchial asthma.

In contrast, in COPD patients, such inflammatory mediators are not important for the bronchomotor tone. In COPD airways, anti-cholinergic agents shows more obvious bronchodilatory effects than β2-stimulants, indicating that vagal nerve-derived acetylcholine is the only bronchoconstrictive (reversible) mechanism in this disease.17

Because tachykinins, such as substance P (SP) and neurokinin A (NKA), are potent stimulants of submucosal glands and goblet cell secretion,16 these peptides seem to be involved in the inflammatory process in asthma and COPD. Increased SP concentrations have been reported in the induced sputum of patients with asthma and COPD compared with healthy individuals (Fig. 2).18 SP is metabolized by neutral endpeptidase (NEP),19 which exists in the respiratory epithelium. In asthmatic airways, epithelium shedding caused by eosinophil-derived major basic protein (MBP)20, 21 leads to dysfunction of the NEP, which may enhance the tachykinins' function. Actually, there was a significant relation between the eosinophil count and SP concentration in the induced sputum from patients with asthma but not in that from COPD subjects.18 These data suggest that SP hypo-degradation due to epithelial loss may be the cause of the elevated SP levels in asthmatic airways. Tachykinin antagonists have been administrated to asthmatic subjects, and have shown clinical benefits in bradykinin- and exercise-induced asthma (Fig. 3, 4).22, 23 There are no reported studies of tachykinin antagonists in COPD subjects.16

Because reactive oxygen and related species including nitric oxide (NO) have a potent proinflammatory action,24, 25 these molecules may be involved in the airway inflammatory process in asthma.26 In animal models, allergen-27 and ozone-induced28 airway inflammation and airway hyperresponsiveness are largely modified by inhibitors of synthesis of reactive oxygen and related species or by scavengers of radical species, supporting this hypothesis. Further, NO hyperproduction due to inducible NO synthase (iNOS) has been shown in asthmatic airways and experimental asthma animal models.29-33 Steroid treatment reduces the NO generation,34 suggesting that NO may be partly responsible for the asthmatic airway inflammation.

Other types of reactive oxygen, such as superoxide anion (O₂^-) may also be exaggerated in asthmatic airways via the upregulation of xanthine oxidase (XO) in microvascular endothelial cells and NADPH oxidase in the infiltrated eosinophils.35 NO rapidly reacts with O₂^- released from inflammatory cells including eosinophils, and results in the formation of the highly proinflammatory molecule peroxynitrite.36

NO seems to be involved in the inflammatory mechanism of the late allergic response (LAR) after allergen challenge, which most resembles asthmatic airway inflammation. We have assessed the NO, O₂^- and peroxynitrite production by measuring the NO concentration in the exhaled air, O₂^- generating enzyme activity, and peroxynitrite-induced nitration product immunostaining, respectively. We quantified the airway microvascular permeability by means of Monastral blue dye trapping between the postcapillary endothelium. The functional role of the NO, O₂^- and peroxynitrite on the microvascular permeability was assessed using each molecule's synthase inhibitor or scavenger. Further, we also quantified the eosinophil accumulation into the airways during the LAR and examined the role of NO, O₂^- and peroxynitrite in the eosinophil response. We have reported that peroxynitrite formed by NO and O₂^- is an important molecule for the microvascular hyperpermeability but not the eosinophil accumulation during the late allergic airway responses.37

Oxidative stress and defense imbalance may be one of the causes of COPD.38-41 The large production of NO during inflammatory-immune processes of the respiratory tract is thought to constitute a host defense mechanism, although this comes at a price because a high level of NO can also cause respiratory tract injury and thus contribute to the pathophysiology of inflammatory airway diseases such as COPD and asthma. Recently, excessive nitric oxide (NO) production, presumably via inducible NO synthase (iNOS), has been reported in asthmatic airways,41 although its presence is controversial in COPD airways.

The adverse effects of NO are thought to be engendered, in part, by its reaction with superoxide anion, which is released from inflammatory cells, yielding the potent oxidant peroxynitrite.36 Peroxynitrite adds a nitro group to the 3-position adjacent to the hydroxyl group of tyrosine to produce the stable product nitrotyrosine. Alternatively, NO reacts with O₂ to form nitrite. The oxidation of nitrite by neutrophil-derived myeloperoxidase (MPO) or by other related peroxidases42 results in the formation of nitryl chloride and nitrogen dioxide (NO₂). This mechanism has also been found in inflammatory conditions. Although tyrosine nitration is generally attributed to peroxynitrite, the peroxidase-dependent nitrite oxidation pathway is also involved. Therefore, nitrotyrosine is a collective indicator for the involvement of reactive nitrogen species. We have reported that abundant nitrotyrosine positive staining cells as well as iNOS positive cells were observed in the induced sputum both in COPD and asthmatic patients compared with healthy subjects.43 The nitrotyrosine positive cells were significantly more obvious in COPD than in asthma, suggesting that the oxidative stress by reactive nitrogen species may be exaggerated in the airways of these diseases, especially in COPD. Further, because the nitrotyrosine positive cell counts were significantly correlated with the airway obstructive changes in COPD (Fig. 4),43 the hyperproduction of reactive nitrogen species may be an important factor in the pathogenesis of COPD. Further, in COPD patients, the steroid-induced improvement in the airway caliber and hyperresponsiveness is significantly correlated with the reduction of the reactive nitrogen species production,44 indicating that modulation of the reactive nitrogen species may be useful for future COPD therapy.

In this review, I have shown some aspects of the differences of the inflammatory processes in asthma and COPD. These differences seem to cause distinct pathological differences between the two diseases.45

ACKNOWLEDGEMENTS

The author thank Mr. Brent Bell for reading this manuscript.

M. I. has previously served as a member of scientific advisory boards for GlaxoSmithKline KK, Nippon Boehringer Ingelheim, Novartis Pharma KK, and AstraZeneca KK. He has received lecture fees from GlaxoSmithKline KK, AstraZeneca KK, Nippon Boehringer Ingelheim, and unrestricted grants from GlaxoSmithKline KK and Nippon Boehringer Ingelheim.

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