Cytokines in innate host defense in the lung
Authors: Robert M. Strieter, John A. Belperio, Michael P. Keane
Journal: Journal of Clinical Investigation (2002)

Historically the lung has been perceived as an organ primarily involved in gas exchange. However, due to its unique relationship with the environment, the lung must defend itself from infection by numerous inhaled micro-organisms. Various innate defenses protect the lung from infection, including the cough reflex, mucociliary clearance (see Knowles and Boucher, this Perspective series, ref. 1), and antimicrobial properties of the mucosal surface (see Ganz, this series, ref. 2; and McCormack and Whitsett, this series, ref. 3). In addition, an extensive alveolar-capillary membrane containing immune and nonimmune cells is exposed to microbial challenges. Consequently, pulmonary tissues generate a brisk innate host response to both inhaled and hematogenous pathogens in order to clear the offending micro-organism and preserve gas exchange.

The successful execution of the innate defense response in the lung is critical to the eventual transition and development of the adaptive immunity. Once containment of the micro-organism has occurred, the response resolves, leading to repair or tissue remodeling. Loss of these later responses leaves the lung susceptible to tissue injury caused by excessive local or distant innate responses. In conditions such as acute respiratory distress syndrome, overexuberant tissue inflammation in response to micro-organisms may lead to irreversible lung injury and mortality.

While a variety of factors — arachidonic acid metabolites, coagulation factors, complement, acute-phase proteins, and antimicrobial peptides among them — are involved in the innate response, cytokines constitute the largest and most pleiotropic group of such mediators and will be the focus of this Perspective. The initiation, maintenance, and resolution of pulmonary innate responses depend upon cellular communication via cytokines. Along with other soluble factors, as well as adhesion molecules, the cytokines contribute to the recognition of pathogens, the recruitment of neutrophils and mononuclear cells, and the removal of the invading micro-organism.

Cytokine signaling occurs through receptor-ligand interactions on specific immune or nonimmune target cell populations. These populations differ not only in their complement of cytokine receptors, but also in their capacities to elaborate and secrete specific cytokines in response to particular stimuli. Interactions among various cell populations have led to the concept of cytokine networking, in which one population of cells may respond directly to specific exogenous or endogenous stimuli, leading to the elaboration of a particular cytokine that exerts distinct effects upon another population of cells. The targets respond by producing cytokines, which may serve as feedback signals to the initiating cell, or, alternatively, by releasing signaling molecules that affect yet another array of target cells. Inflammatory effector cells, such as neutrophils and monocytes, may be locally recruited and activated in response to specific chemotactic signals, resulting in further amplification of a cytokine cascade by nonimmune resident cells.