Tumour necrosis factor-alpha production in fibrosing alveolitis is macrophage subset specific

Background: Previous studies have revealed that tumour necrosis factor (TNF )-alpha is upregulated in fibrosing alveolitis (FA) in humans. The aim of t his study was to compare the TNF-alpha secretory profile of alveolar macrop hages (AMs) and peripheral blood monocytes (Mos) of patients with cryptogen ic FA and systemic sclerosis (SSc), a rheumatological disorder in which lun g fibrosis can occur. In particular, we wished to assess whether TNF-alpha levels differ between SSc patients with FA (FASSc) and a nonfibrotic group. Methods: The reverse haemolytic plaque assay was used to evaluate the secre tion of cytokine at a single cell level while immunostaining allowed subtyp ing of AMs and Mos. Results: This study demonstrated a difference in total TNF-alpha levels pro duced by AMs when the levels in subjects with FA (cryptogenic FA and FASSc) were compared to levels in either SSc patients without FA (P = 0.0002) or normal healthy controls (P < 0.001). In addition, AMs from patients with FA SSc secreted more TNF-<alpha> than those of patients with no FA (P = 0.003) . In contrast, there were no significant differences in Mo TNF-alpha secret ion between the groups. A positive correlation was found between total TNF- alpha level and number of neutrophils obtained by bronchoalveolar lavage fr om patients with FA (r = 0.49, P < 0.04). Finally, it was demonstrated that there was significant heterogeneity of TNF-<alpha> secretion and that a nu merically significant subset of mononuclear phagocytes, RFD7, was responsib le for more than 80% of TNF-alpha production. Conclusion: By demonstrating the primary cell source of TNF-alpha in FASSc, more accurately targeted, possibly localized, anti-TNF strategies might be employed with success in the future.