Neutrophilic Alveolitis in Idiopathic Pulmonary Fibrosis: The Role of Interleukin-8

Abstract

Abstract Idiopathic pulmonary fibrosis is an immunologically mediated pulmonary disorder in which activated alveolar macrophages (AM) and neutrophils play cardinal roles in the pathogenesis of the inflammatory lung lesion. The factors responsible for the induction and perpetuation of the neutrophilic alveolitis are not known. Recently, a novel cytokine (interleukin-8) was described that is released by activated mononuclear phagocytes and a variety of other cell types, and it exhibits potent chemotactic activity for polymorphonuclear leukocytes (PMN). Increased expression of IL-8 has been described in other inflammatory disorders characterized by neutrophilic infiltration, including psoriasis, rheumatoid arthritis, and the sepsis syndrome, but no studies have assessed this cytokine in the context of interstitial pulmonary disorders. We have previously shown that normal human AM release IL-8 upon appropriate stimulation, but data assessing the expression of IL-8 by human AM in specific pulmonary disease states are lacking. In this study, we examined the expression of steady-state mRNA for IL-8 by human alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis and from healthy volunteers. Because it is known that adherence to plastic culture plates may up-regulate gene expression for IL-8 in the absence of additional stimulation, we extracted mRNA immediately from the cell pellet obtained by BAL rather than using cultured alveolar macrophage monolayers. Northern blot analysis was performed to determine IL-8 mRNA expression. We found that BAL cells from patients with IPF constitutively expressed mRNA for IL-8, and the amount of IL-8 mRNA (as assessed by laser densitometry) correlated with the percent of neutrophils on BAL. By contrast, BAL cells isolated from healthy subjects failed to express mRNA for IL-8 constitutively, whereas only low levels of IL-8 mRNA were detected in patients with pulmonary sarcoidosis. The cellular source of the augmented expression of IL-8 mRNA in patients with IPF appeared to be AM, as AM isolated from IPF patients constitutively expressed cell-associated protein, whereas AM from patients with sarcoidosis and healthy subjects produced significantly lesser quantities of immunoreactive IL-8. These data suggest that increased expression of IL-8 may be a feature of IPF and support a role for IL-8 in the neutrophilic alveolitis of IPF.