MACROPHAGE INFLAMMATORY PROTEIN-1 ALPHA EXPRESSION IN INTERSTITIAL LUNG-DISEASE

Mononuclear phagocyte (MO) recruitment and activation is a hallmark of a number of chronic inflammatory diseases of the lung, including sarc oidosis and idiopathic pulmonary fibrosis (IPF). We hypothesized that macrophage inflammatory protein-1 (MIP-1alpha), a peptide with leukocy te activating and chemotactic properties, may play an important role i n mediating many of the cellular changes that occur in sarcoidosis and IPF. In initial experiments, we demonstrated that human rMIP-1 alpha exerted chemotactic activities toward both polymorphonuclear leukocyte s and monocytes, and these activities were inhibited by treatment with rabbit anti-human MIP-1 alpha antiserum. In support of the potential role of MIP-1 alpha in interstitial lung disease, we detected MIP-1 al pha in the bronchoalveolar lavage fluid of 22/23 patients with sarcoid osis (mean 443 +/- 76 pg/ml) and 9/9 patients with IPF (mean 427 +/- 8 1 pg/ml), whereas detectable MIP-1 alpha was found in only 1/7 healthy subjects (mean 64 +/- 64 pg/ml). In addition, we found a 2.5- and 1.8 -fold increase in monocyte chemotactic activity in BALF obtained from patients with sarcoidosis and IPF respectively, as compared to healthy subjects, and this monocyte chemotactic activity, but not neutrophil chemotactic activity, was reduced by approximately 22% when bronchoalv eolar lavage fluid from sarcoidosis and IPF patients were preincubated with rabbit antihuman MIP-1 alpha antibodies. To determine the cellul ar source(s) of MIP-1 alpha within the lung, we performed immunohistoc hemical analysis of bronchoalveolar lavage cell pellets, transbronchia l biopsies, and open lung biopsies obtained from patients with IPF and sarcoidosis. Substantial expression of cell-associated MIP-1 alpha wa s detected in MO, including both alveolar AMO and interstitial MO. In addition, interstitial fibroblasts within biopsies obtained from sarco id and IPF patients also expressed immunoreactive MIP-1 alpha. Minimal to no detectable MIP-1 alpha was expressed in alveolar MO from health y subjects or interstitial cells in lung biopsy specimens obtained fro m patients undergoing thoracotomy for malignancy. Furthermore, pulmona ry fibroblasts isolated from patients with IPF produced greater amount s of MIP-1 alpha after challenge with IL-1 beta than did similarly tre ated pulmonary fibroblasts recovered from patients without fibrotic lu ng disease. Our findings suggest that MIP-1 alpha is expressed in incr eased amounts within the airspace and interstitium of patients with sa rcoidosis and IPF, and that this cytokine may be an important mediator of both MO activation and recruitment that characterize these disease states.