The pathologic presentation of a number of chronic lung disease is often associated with an inflammatory response, with subsequent fibroproliferation and deposition of extra-cellular matrix. Many chronic lung disorders share common characteristics, including an unknown etiology, ill-defined mechanisms of disease progression, inability to effectively resolve, and end-stage fibrosis. Unfortunately, these progressive chronic lung diseases are usually refractory to treatment and are associated with substantial morbidity and mortality. The inability to identify efficacious therapeutic options to treat the actively progressing forms of these lung disorders likely reflects the scientific community's limited mechanistic understanding of these disorders. However, investigative inroads have been made that suggest that cytokine networks are operative in dictating the progression of these diseases. For example, it is known that various cytokines can promote and maintain the chronicity of inflammation by sustaining the recruitment of leukocyte subpopulations and inducing fibroblast activation, proliferation, and collagen deposition during the maintenance of chronic lung disease.

Clearly, the etiology of chronic lung disease, which possesses a fibrotic outcome, is diverse and includes such insults as radiation injury, cytotoxic drugs, particulates, and idiopathic events. However, we present a working model based on immune dependent cytokine phenotypes that appear to be important in dictating the progression of lung inflammation and end-stage outcome. The involvement of various cytokines in the initiation and maintenance of chronic immune-mediated lung disease, which eventually may mature to end-stage fibrosis, may be directed by a sequence of host cytokine responses that have gone awry. Under a normal host defense paradigm, it is likely that the initial cell-mediated reaction involves the expression of [gamma] interferon and mediators that would fall under the rubric of a type 1 response. The immune process involving a high interferon (IFN)-[gamma] response is extremely efficient in activating the phagocytosis and killing activity of neutrophils, monocytes, and macrophages, as well as inducing MHC class II expression on antigen-presenting cells (APC). Although the elevation in IFN-[gamma] is indeed important in activating mononuclear cells, it also serves a key role in the regulation of fibroblast activation. The ability of IFN-[gamma] to suppress fibroblast proliferation and collagen deposition has long been recognized as a biological activity of this type 1 cytokine.