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Peripheral blood neutrophils are hyperresponsive to IL-8 and Gro- in cryptogenic fibrosing alveolitis

Division of Therapeutics, University Hospital of Nottingham, UK

CORRESPONDENCE: I.P. Hall, Division of Therapeutics, South block C Floor, Queens Medical Centre, University Hospital, Nottingham, NG7 2UH, UK. Fax: 44 1159422232

Keywords: cryptogenic fibrosing alveolitis, CXCR2 antagonist, growth-related oncogene-, neutrophil shape change, SB272844

Received: June 26, 2000
Accepted May 4, 2001

Cryptogenic fibrosing alveolitis (CFA) is characterized by increased pulmonary recruitment of peripheral blood neutrophils (PBNs) by interleukin (IL)-8 and other chemotactic mediators. This study investigated whether, in CFA, the PBN motility response is primed by IL-8 and growth-related oncogene (Gro)-, as demonstrated in other neutrophilic inflammatory diseases, and whether the motility response of PBNs to IL-8 and Gro- can be abrogated using a selective antagonist for the neutrophil receptor for IL-8 and Gro-, CXCR2.

The percentage of PBNs to undergo shape change (%SC), spontaneously and in response to IL-8 and Gro-, was measured in patients with CFA (n=10) and controls (n=10), and the effect of the CXCR2 antagonist SB272844 studied. Plasma levels of IL-8, and Gro- were measured using an enzyme-linked immunosorbent assay (ELISA).

The %SC of unstimulated PBNs and the potency of Gro- and IL-8 to produce neutrophil polarization was greater in CFA than in controls; dose which produces 50% of maximal effect (EC₅₀) of IL-8 was 3.6±0.7 nM for CFA versus 6.3±1.0 nM for controls; p<0.05. SB272844 inhibited Gro- induced but not IL-8 induced neutrophil shape change (equilibrium constant (K_D) 123±18 nM). Plasma concentrations of Gro- were increased in patients with CFA. PBNs are spontaneously activated and undergo a greater motility response to IL-8 and Gro- in CFA.

Interleukin-8 and growth-related oncogene-, circulating in substimulatory amounts in cryptogenic fibrosing alveolitis, may prime the peripheral blood neutrophils motility response, thus increasing their capacity for migration to the lung. Selective CXCR2 antagonists may be useful to block the Gro--induced priming response whilst preserving neutrophil functions mediated by CXCR1, the alternative neutrophil receptor for interleukin-8.

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