CONSTITUTIVE ACTIVATION OF 5-LIPOXYGENASE IN THE LUNGS OF PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characte rized by inflammation, fibroblast proliferation, and accumulation of e xtracellular matrix proteins, Leukotrienes (LTs) are pro-inflammatory and pro-fibrogenic mediators derived from the 5-lipoxygenase (5-LO) pa thway of arachidonic acid metabolism, They are thought to play a role in a number of disease processes, but have received relatively little attention in investigations into the pathogenesis of IPF. In this stud y, we measured the levels of immunoreactive LTs B-4 and C-4 in homogen ates of lung tissue obtained from patients with newly diagnosed, untre ated IPF, as compared to levels measured in homogenates of uninvolved nonfibrotic lung tissue from patients undergoing resectional surgery f or bronchogenic carcinoma, Compared to homogenates of nonfibrotic cont rol lung, homogenates from IPF patients contained 15-fold more LTB(4) and 5-fold more LTC(4). IPF homogenate levels of LTB(4) were significa ntly correlated with histologic indices of both inflammation (r = 0.86 1) and fibrosis (r = 0.926). Activation of 5-LO is known from in vitro studies to be associated with localization of the enzyme at the nucle ar membrane. Immunohistochemical staining for 5-LO protein in alveolar macrophages (AMs) demonstrated that such an ''activated'' localizatio n pattern was significantly more frequent in IPF lung (19.2 +/- 3.3% o f cells) than in control lung (9.3 +/- 0.9%); this localization patter n was rarely seen (3.2%) in sections from a truly normal transplant do nor lung, Consistent with these data, AMs obtained from IPF patients b y bronchoalveolar lavage, purified by adherence, and cultured in the a bsence of a stimulus for 16 h elaborated significantly greater amounts of LTB(4) and LTC(4) than did control AMs obtained from normal volunt eers. These data indicate that the 5-LO pathway is constitutively acti vated in the lungs of patients with IPF, and the AM represents at leas t one cellular source of LT overproduction in this disorder, We specul ate that LTs participate in the pathogenesis of IPF, and their overpro duction in this disorder may be amenable to specific pharmacotherapy.