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 this study was to compare the TNF-alpha secretory profile of alveolar macrophages (AMs) and peripheral blood monocytes (Mos) of patients with cryptogenic FA and systemic sclerosis (SSc), a rheumatological disorder in which lung 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 secretion of cytokine at a single cell level while immunostaining allowed subtyping of AMs and Mos. Results: This study demonstrated a difference in total TNF-alpha levels produced 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 FASSc secreted more TNF- than those of patients with no FA (P = 0.003). In contrast, there were no significant differences in Mo TNF-alpha secretion between the groups. A positive correlation was found between total TNF-alpha level and number of neutrophils obtained by bronchoalveolar lavage from patients with FA (r = 0.49, P < 0.04). Finally, it was demonstrated that there was significant heterogeneity of TNF- secretion and that a numerically significant subset of mononuclear phagocytes, RFD7, was responsible 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.