Does a primary host defense abnormality involving monocytes-macrophages underlie the pathogenesis of lung disease in cystic fibrosis?

Abstract

The primary cause of morbidity and mortality in cystic fibrosis (CF) patients is chronic pulmonary disease. Pulmonary disease in CF is characterized in part by: (a) obstruction of the bronchi and bronchioles by inspissated secretions (mucus is hypersecreted and may also be abnormal), (b) recurrent or persistent bacterial infections, and (c) a chronic inflammatory state. We propose herein that much of the pathophysiology of lung disease in CF stems from a genetically inherited metabolic defect in monocyte-macrophages (M-MØ), and we review evidence which indicates that CF M-MØ are innately metabolically abnormal. Once activated by various stimuli, CF M-MØ become metabolically hyperactive and hypersecretory as evidenced by the production of excessive levels of a variety of mediators which could have definite roles in both the initiation of pulmonary obstruction and the accelerated development of a chronic inflammatory response in CF. Evidence is also reviewed which indicates that other CF M-MØ functions crucial to the afferent and efferent phases of the immune response to bacterial infections in the lung may be adversely affected. Mechanisms proposed to explain the abnormal production of mediators by CF M-MØ are discussed, and it is concluded that hyperproduction of mediators by CF M-MØ and their metabolic hyperactivity probably result from a defect in autoregulation. The nature of the metabolic defect in CF M-MØ indicates that CF should be classified as a “new” primary host defense abnormality or alternatively as a “new” primary immune deficiency disease.