Pulmonary Host Defenses: The Role of Cytokines in Mediating Lung Inflammation

, , , , University of Michigan Medical School, Ann Arbor, Mich.

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In This Article

Abstract and Introduction

Abstract

The clearance of microbes from the respiratory tract requires the generation of a vigorous and localized inflammatory response. The magnitude of this inflammatory response is tightly controlled by host-derived cytokines, which mediate lung inflammation by serving as leukocyte chemoattractants, leukocyte-activating factors, or afferent signals in the induction or regulation of other effector molecules. Tumor necrosis factor (TNF)-alpha appears to be one of the most important components of cytokine-mediated host defense. Additionally, at least two subfamilies of chemokines contribute to pulmonary antimicrobial host defense, namely C-X-C and C-C chemokines. Interferon-gamma serves as a potent activator of resident and recruited leukocytes, whereas IL-12 enhances the inflammatory response via the induction of IFN-gamma and TNF-alpha. Conversely, IL-10 impairs antimicrobial host defense by directly inhibiting leukocyte microbicidal activity and local proinflammatory cytokine expression. Ultimately, the balance between pro- and anti-inflammatory cytokines determines outcome in lung host defense. As our understanding of the role of cytokines in lung host defense has increased, the focus has shifted to identification of specific cytokines that can be targeted for immunotherapy. However, the precise clinical setting and mechanism by which to administer or inhibit cytokines has not yet been fully realized. This article reviews the role of specific cytokines involved in lung innate and acquired immunity against bacterial, mycobacterial, fungal, and parasitic pathogens. Novel approaches to immunotherapy -- including compartmentalized cytokine delivery using adenoviral gene transfer -- as adjuvant therapy in the treatment of pneumonia are also addressed.

Introduction

The emergence of multi-drug-resistant microbes in the immunocompromised host has made treatment of bacterial, fungal, and mycobacterial infections of the lung increasingly difficult.[1,2,3] This rather ominous trend underscores the need to gain a full understanding of the immune host response in order to develop immunotherapies that can directly augment these responses.

Effective host defense against common bacterial pathogens of the respiratory tract is primarily dependent upon the rapid clearance of the etiologic agent from the lung.[4,5] Innate (natural) immunity is the principal pathway for effective elimination of bacterial organisms that have reached the alveolus. The three principal phagocytic cells that constitute innate immunity in the lung include resident alveolar macrophages, recruited neutrophils, and recruited monocytes/macrophages. In addition, these cells, as well as resident T and NK cells, participate in innate immune response in the lung via the elaboration of important activating and/or chemotactic cytokines. In contrast to bacterial infection, host responses to intracellular bacteria, fungi, mycobacteria, and viruses are more complex and require both the phagocytic system, as well as antibody-mediated and cell-mediated immunity.[6,7] While neutrophils play a role in host defense against some of these pathogens, the recruitment and/or activation of macrophages and CD4+ T cells is essential for the effective clearance of many intracellular pathogens from the lung.

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