Airway Remodeling & Eosinophils

Figure 1. CCR3-bearing eosinophils infiltrate the asthmatic respiratory membrane via Eotaxin/CCL11 secreted by airway epithelial cells, fibroblasts, and smooth muscle cells. Once present in asthmatic airways, eosinophils contribute to the inflammatory component of asthma as well as to airway remodeling via basement membrane fibrosis mediated by eosinophil cationic protein (ECP).

The chronic inflammation experienced by asthmatics leads to irreversible airway remodeling. Airway remodeling is characterized by increased mucus, epithelial damage, basement membrane fibrosis, and fibroblast and smooth muscle cell hypertrophy and hyperplasia.1,2 However, perhaps the most commonly described attribute of asthmatic airways is eosinophilia. Eosinophils expressing the CCR3 chemokine receptor are drawn from pulmonary circulation primarily by Eotaxin/CCL11, which is overexpressed in asthmatic respiratory membrane epithelial cells, fibroblasts, and smooth muscle cells (Figure 1).3 It has been known for some time that eosinophils infiltrate the respiratory membranes of asthmatics and contribute significantly to the inflammatory component of asthma. Further, several lines of evidence suggest an association between eosinophils and fibrosis. For example, eosinophils release cytotoxic mediators, pro-inflammatory cytokines, and TGF-ß, which has well-known fibrotic effects. However, no direct link between eosinophils and airway remodeling has been established. New evidence provided by Zagai et al. suggests such a link, and implicates eosinophil cationic protein (ECP) as a mediator of basement membrane fibrosis.4

ECP is a 18 to 21 kDa, glycosylated, arginine-rich protein of the ribonuclease superfamily. ECP is found, along with eosinophil-derived neurotoxin (EDN), major basic protein (MBP), and eosin-ophil peroxidase, in the large specific granules of eosinophils.5,6 Eosinophil degranulation is induced by Eotaxin, as well as other chemokines, via CCR3 and downstream signaling by ERK and p38 MAP kinases.7 Once released, ECP is a potent cytotoxin and neurotoxin, disrupting target cell membranes possibly by pore formation. ECP is also a strong helminthotoxin, capable of destroying schistosoma at ECP concentrations as low as 10-7 M.5,6

Zagai et al. describe the effects of eosinophils on collagen gel contraction as an in vitro model of one aspect of fibrosis.4 The authors found that when fibroblasts were cultured either with peripheral blood eosinophils or with an eosinophil-like cell line, collagen gel contraction was dependent on time in culture and on eosinophil number. When ECP content of both the collagen gel and the culture medium was examined, ECP levels were observed to be greater in co-cultures than in cultures of eosinophils alone, and no ECP was detected in cultures of fibroblasts alone. Finally, when ECP was added to the collagen gel in fibroblast cultures lacking eosinophils, dose-dependent collagen gel contraction was observed.4 These data suggest direct involvement of eosinophils and ECP in fibrosis and therefore in asthmatic airway remodeling (Figure 1). ECP may have other effects on respiratory membrane tissues as well, including epithelial damage.

Since eosinophils are rarely observed in healthy airways and the number of eosinophils present in asthmatic airways correlates with increasing disease severity,8 it is not surprising that eosinophils may be involved not only in the inflammatory component, but also in the fibrotic component of asthma. Likewise, several other fibrotic diseases are associated with eosinophilia.4 While prevention of eosinophil infiltration in asthmatic airways may be difficult, ECP specifically might represent a more reasonable drug target for both the inflammatory and fibrotic components of asthma.


  1. Wenzel, S. (2003) Clin. Exp. Allergy 33:1622.
  2. Lynch, E.L. et al. (2004) Cytokine Growth Factor Rev. 14:489.
  3. Lukas, N.W. (2001) Nature Rev. Immunol. 1:108.
  4. Zagai, U. et al. (2004) Clin. Exp. Immunol. 135:427.
  5. Rosenberg, H.F. et al. (1989) J. Exp. Med. 170:163.
  6. Barker, R.L. et al. (1989) J. Immunol. 143:952.
  7. Kampen, G.T. et al. (2000) Blood 95:1911.
  8. Bousquet, J.B. et al. (1990) N. Engl. J. Med. 323:1033.