Eosinophil Progenitors in Airway Diseases: Hemopoietic Processes as Targets of Therapy

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Modulation of Eosinophil Differentiation by CS

Hemopoietic mechanisms can be targeted by antiallergic therapies (Table 1). For example, topical treatment with CS can affect the hemopoietic response by abrogation of cytokine production by airways tissues, reduction in peripheral blood Eo/B progenitors, and decreases in BM myeloid progenitors (in a canine asthma model). Most likely, inhaled CS in these models exert their effects on the marrow progenitor response indirectly by interfering with cytokines elaborated from the inflamed tissue, which can then act systemically on the BM. However, a direct effect on progenitors cannot be excluded because there is evidence that, both in vitro and in vivo, low systemic levels of CS (10~ mol/L) can block differentiation of the Eo/B progenitor in humans and of the myeloid progenitor in dogs. Studies of the apparently paradoxical stimulation by budesonide, a topically active CS that suppresses allergic inflammation in vivo, of IL-5-induced eosinophilopoiesis in vitro have revealed that one possible mechanism of action of CS is the early upregulation of an eosinophil lineage-specific transcription factor, GATA-1, followed by later suppression. These studies support the concept that topical CS alone might represent an insufficient therapeutic option in long-term management of rhinitis and asthma because of a lack of control of the progenitor-marrow contribution to allergic inflammation.

Modulation of Eosinophil Differentiation by Other Antiallergic Compounds

We have provided evidence for the blockade of eosinophil differentiation by CysLT receptor antagonists, antibodies to IL-5, and nonsedating, histamine type 1 antihistamines, both in vivo and ex vivo/in vitro, in human cells and animal models of airways inflammation. In murine experimental allergic rhinitis, CysLT-1 receptor (CysLT1-R) antagonism in vivo limits IL-5-responsive eosinophilopoiesis, acting at several stages of eosinophil differentiation and maturation. The antiallergic effects of CysLT1-R antagonists are consistent with the concept that CysLTs and IL-5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation, targeting both IL-5Ra and CysLT1-R on progenitors. Thus, a potential therapeutic target in eosinophilic airways disease is the Eo/B progenitor (Fig 2).

Implications for Other Diseases

A brisk BM response that includes the release of immature cells has been documented during the course of a variety of nonatopic inflammatory events in the lung, such as pneumonia, endotoxemia, cigarette smoking, asthma, and exposure to air pollut-ants. This suggests that BM progenitors contribute to lung repair following infection or may determine inflammation and/or disease severity in COPD; a defective BM response could underlie the pathogenesis of COPD and related chronic upper and lower airway conditions.

Conclusions

This review has examined how the BM supplies and delivers hemopoietic progenitors to sites of allergic inflammation, and discussed factors that can modulate these progenitors physiologically and, potentially, therapeutically. Evidence that current and experimental therapies have a systemic effect may change the way we treat these increasing global health concerns.

Table 1—Effects of Several Antiallergic Treatment Options on Hemopoietic Processes and Eosinophils

Treatment	Sputum Eosinophils	Nasal Eosinophils	Eo/B Progenitors
Antihistamine	Uncertain	Reduce/no effect	Reduce
LTRA	Reduce	Reduce	Reduce
Topical steroid	Reduce	Reduce	Reduce
Systemic steroid	Reduce	Reduce	Uncertain

Figure 2. Progenitors differentiate to mature eosinophils within the BM but also traffic as progenitors through the bloodstream and into airway tissue sites where they can differentiate into mature eosinophils. The effects of some treatments on eosinophil differentiation and survival are illustrated. Parentheses indicate a cofactor. H1 = histamine type 1; LTC4 = leukotriene C4; LTD4 = leukotriene D4.