Standiford T J, Rolfe M W, Kunkel S L, Lynch J P, Burdick M D, Gilbert A R, Orringer M B, Whyte R I, Strieter R M
Department of Medicine, University of Michigan Medical School, Ann Arbor 48109-0360.
J Immunol. 1993 Sep 1;151(5):2852-63.
Mononuclear phagocyte (M phi) recruitment and activation is a hallmark of a number of chronic inflammatory diseases of the lung, including sarcoidosis and idiopathic pulmonary fibrosis (IPF). We hypothesized that macrophage inflammatory protein-1 (MIP-1 alpha), a peptide with leukocyte activating and chemotactic properties, may play an important role in 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 leukocytes 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 alpha in the bronchoalveolar lavage fluid of 22/23 patients with sarcoidosis (mean 443 +/- 76 pg/ml) and 9/9 patients with IPF (mean 427 +/- 81 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 bronchoalveolar lavage fluid from sarcoidosis and IPF patients were preincubated with rabbit antihuman MIP-1 alpha antibodies. To determine the cellular source(s) of MIP-1 alpha within the lung, we performed immunohistochemical analysis of bronchoalveolar lavage cell pellets, transbronchial biopsies, and open lung biopsies obtained from patients with IPF and sarcoidosis. Substantial expression of cell-associated MIP-1 alpha was detected in M phi, including both alveolar AM phi and interstitial M phi. In addition, interstitial fibroblasts within biopsies obtained from sarcoid and IPF patients also expressed immunoreactive MIP-1 alpha. Minimal to no detectable MIP-1 alpha was expressed in alveolar M phi from healthy subjects or interstitial cells in lung biopsy specimens obtained from patients undergoing thoracotomy for malignancy. Furthermore, pulmonary fibroblasts isolated from patients with IPF produced greater amounts of MIP-1 alpha after challenge with IL-1 beta than did similarly treated pulmonary fibroblasts recovered from patients without fibrotic lung disease. Our findings suggest that MIP-1 alpha is expressed in increased amounts within the airspace and interstitium of patients with sarcoidosis and IPF, and that this cytokine may be an important mediator of both M phi activation and recruitment that characterize these disease states.
单核吞噬细胞（M phi）的募集和激活是许多肺部慢性炎症性疾病的标志，包括结节病和特发性肺纤维化（IPF）。我们推测巨噬细胞炎性蛋白-1（MIP-1α），一种具有白细胞激活和趋化特性的肽，可能在介导结节病和IPF中发生的许多细胞变化中起重要作用。在最初的实验中，我们证明人重组MIP-1α对多形核白细胞和单核细胞都具有趋化活性，并且这些活性在用兔抗人MIP-1α抗血清处理后受到抑制。为支持MIP-1α在间质性肺疾病中的潜在作用，我们在22/23例结节病患者（平均443±76 pg/ml）和9/9例IPF患者（平均427±81 pg/ml）的支气管肺泡灌洗液中检测到MIP-1α，而在仅1/7例健康受试者（平均64±64 pg/ml）中检测到可检测到的MIP-1α。此外，我们发现与健康受试者相比，分别从结节病和IPF患者获得的BALF中的单核细胞趋化活性增加了2.5倍和1.8倍，并且当结节病和IPF患者的支气管肺泡灌洗液与兔抗人MIP-1α抗体预孵育时，这种单核细胞趋化活性（而非中性粒细胞趋化活性）降低了约22％。为了确定肺内MIP-1α的细胞来源，我们对从IPF和结节病患者获得的支气管肺泡灌洗细胞沉淀、经支气管活检和开胸肺活检进行了免疫组织化学分析。在M phi中检测到大量细胞相关的MIP-1α表达，包括肺泡巨噬细胞（AM phi）和间质M phi。此外，从结节病和IPF患者获得的活检组织中的间质成纤维细胞也表达免疫反应性MIP-1α。在接受恶性肿瘤开胸手术患者的肺活检标本中，健康受试者的肺泡M phi或间质细胞中几乎没有检测到可检测到的MIP-1α表达。此外，与从无纤维化肺病患者中回收的经类似处理的肺成纤维细胞相比，从IPF患者中分离的肺成纤维细胞在用IL-1β刺激后产生更多量的MIP-1α。我们的研究结果表明，MIP-1α在结节病和IPF患者的气腔和间质中表达量增加，并且这种细胞因子可能是这些疾病状态所特有的M phi激活和募集的重要介质。
