Most inflammatory mediators are rapidly inactivated once they leave the cell so that they act across distances of only a few microns. It is therefore likely that microlocalisation between inflammatory and structural cells is a fundamental organising principle of airway inflammation and repair.

Enthusiasm for the view that microlocalisation is important in obstructive airway diseases has been fuelled by studies which showed inflammatory cells within the airway smooth muscle in asthma and chronic obstructive pulmonary disease (COPD) but not in normal controls. In asthma the airway smooth muscle is infiltrated by mast cells, predominantly of the chymase positive phenotype. Mast cell numbers correlate inversely with airway responsiveness,¹ which suggests that interactions between mast cells and smooth muscle cells are central in the development of the disordered physiology in asthma. The strength of this assertion is underpinned by the paucity of mast cells within the airway smooth muscle in eosinophilic bronchitis, a condition that presents with chronic cough and shares many of the immunopathological features of asthma but is not associated with airflow obstruction or airway hyperresponsiveness.^1–3 Importantly, there is evidence that mast cells infiltrating the airway smooth muscle bundle are activated; a necroscopic study of fatal and non-fatal asthma has shown that there is a marked increase in mast cell degranulation in the airway smooth muscle in both the large and small airways.⁴

A recent study has investigated whether a similar phenomenon occurs in COPD. Baraldo et al⁵ found increased numbers of neutrophils and CD8+ cells—but not mast cells—in the small airways of smokers with COPD, and the neutrophil number was inversely related to percentage predicted forced expiratory volume in 1 second (FEV₁). This is consistent with an earlier study which showed that the number of neutrophils in the airway smooth muscle in smokers is related to air trapping as determined by CT scanning.⁶ However, in this study Berger et al found that the number of chymase positive mast cells was more closely related with air trapping. Most of the subjects in these studies had undergone lung resection for cancer so, although the airways studied were considered to be from unaffected areas, there remains the possibility that the underlying lung cancer contributed to the inflammatory changes. Nevertheless, the body of evidence strongly suggests that microlocalisation of inflammatory cells within the airway smooth muscle bundle is an important feature of obstructive airway diseases. This raises two key questions:

• Why do specific inflammatory cells accumulate in the airway smooth muscle in asthma and COPD?

• How do interactions between these inflammatory cells and airway smooth muscle cells lead to disordered airway function?

WHY DO SPECIFIC INFLAMMATORY CELLS ACCUMULATE IN THE AIRWAY SMOOTH MUSCLE IN ASTHMA AND COPD?

Selective recruitment of inflammatory cells to the airway smooth muscle is likely to be mediated by smooth muscle derived chemoattractants and by maintenance of the correct microenvironment to maintain cell differentiation and survival. Airway smooth muscle has a significant secretory capacity, so it clearly has the potential to recruit inflammatory cells.⁷ For example, CXCL8 (IL-8) and CXCL10 (IP-10) released by activated airway smooth muscle in COPD may mediate neutrophil and CD8+ cell migration into the airway smooth muscle bundle.^8,9 A plethora of chemotactic factors for mast cells are released by airway smooth muscle—notably, stem cell factor (SCF),¹⁰ CCL11 (eotaxin),¹¹ CXCL8 (IL-8),⁸ and transforming growth factor (TGF)-β.¹⁰ We have recently shown that CXCR3 is the most abundantly expressed chemokine receptor on human lung mast cells within airway smooth muscle, that human lung mast cell migration is induced by the CXCR3 ligand CXCL10, and that CXCL10 is released preferentially from asthmatic airway smooth muscle cells compared with those from healthy controls.¹² Future studies investigating the effects of inhibiting this pathway will be of particular interest.

It is likely that a number of other chemokines play a role in the recruitment of inflammatory cells into the airway and it may be that the release of chemotaxins by airway smooth muscle varies in response to different stimuli such as cigarette smoke, infection, or allergen exposure. Future studies should explore the relative importance of these triggers and the associated chemotaxins that are released in promoting inflammatory cell infiltration into the airway smooth muscle. It is also important to investigate why some inflammatory cells, notably eosinophils, are rarely seen in the airway smooth muscle in spite of appropriate chemotactic signals.

HOW DO INTERACTIONS BETWEEN THESE INFLAMMATORY CELLS AND AIRWAY SMOOTH MUSCLE CELLS LEAD TO DISORDERED AIRWAY FUNCTION?

Activation of the inflammatory cells within the airway smooth muscle bundle would be predicted to have important consequences on airway smooth muscle function. Following mast cell degranulation the mediators histamine, PGD₂ and LTC₄ are released which are all potent agonists for airway smooth muscle contraction.¹³ Mast cell cytokines may further contribute to airway hyperreponsiveness. The mast cells in the airway smooth muscle bundles in asthma express IL-13,¹⁴ and IL-13 has been shown to attenuate relaxation to β agonists and to augment contractility to acetylcholine.^15,16 The effect of neutrophil derived mediators on airway smooth muscle function is less clear, with conflicting reports from animal studies showing that elastase can increase and diminish smooth muscle responsiveness.^17,18

The interactions between inflammatory cells and airway smooth muscle cells may have more long term consequences. A number of mast cell mediators including histamine,¹⁹ tryptase,²⁰ and LTD₄,²¹ as well as the neutrophil product elastase,²² promote airway smooth muscle proliferation. Increased airway smooth muscle mass is a well established feature of both asthma²³ and COPD.²⁴ In asthma this occurs predominantly in the large airway and in COPD in the small airways. A study using a computational model of the effects of increased muscle mass has suggested that it is the most important abnormality responsible for the increased airflow resistance observed in response to bronchoconstricting stimuli in both asthma and COPD.²⁵ The relative contribution of airway wall smooth muscle mass to overall airway wall thickness in the small airways is much greater than that in the large airways. Thus, increased smooth muscle mass in the small airways is likely to make a significant contribution to the development of fixed airflow obstruction characteristic of COPD and sometimes seen in persistent chronic severe asthma. The role of interactions between inflammatory cells and smooth muscle cells in the development of airway wall remodelling in asthma and COPD offers exciting opportunities for future research.

FUTURE STUDIES

The recognition of the importance of microlocalisation is not confined to inflammatory cells and airway smooth muscle cells but is probably equally critical in interactions with other structural cells such as the epithelium, fibroblasts, mucosal glands, and nerve cells. Eosinophilic bronchitis, cough variant asthma, and idiopathic chronic cough are associated with increased concentration of mast cell products in sputum,^26,27 and we have suggested that localisation of mast cells to sensory nerve endings might be important in the development of cough reflex hypersensitivity and cough. A rather similar interaction is thought to be important in the genesis of itch.^28,29 Understanding the fundamental steps that are involved in the migration of inflammatory cells towards structural cells such as the airway smooth muscle and the interactions between these cells may provide us with novel targets for the future treatment of asthma, COPD, and cough. Researchers interested in the immunopathology of airway diseases therefore need to be mindful of the importance of “location, location, location”.