© 2004 American Thoracic Society
Lysozyme in Pulmonary Host DefenseNew Tricks for an Old DogUniversity of Washington Seattle, Washington More than 80 years ago, Alexander Fleming observed that a drop of nasal secretions could rapidly dissolve a suspension of bacteria (1). Fleming named the active component "lysozyme," described its wide distribution in body fluids and tissues, and recognized its limited antimicrobial spectrum. Over the ensuing decades lysozyme has been characterized extensively. A 14-kD cationic protein consisting of a single polypeptide chain, lysozyme is secreted on to epithelial surfaces and is found in the primary and secondary granules of neutrophils, as well as the granules of mononuclear phagocytes (2). Lysozyme is the most abundant antimicrobial polypeptide in respiratory tract secretions, and local levels rise with inflammation (2). The antimicrobial actions of lysozyme are protean. Lysozyme damages the cell walls of bacteria and fungi by hydrolyzing the ß1–4 glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, which are structural components of bacterial peptidoglycan and fungal chitin, respectively. Lysozyme also can kill bacteria by nonenzymatic means that have not been fully characterized (2, 3). Lysozyme generally exhibits greater microbiocidal effects against gram-positive than gram-negative bacteria. The activity of lysozyme against gram-negative organisms is influenced by ionic concentration, osmolarity, and the presence of synergistic cofactors (2, 4, 5). In the years since Fleming's original observations, a great deal has been learned regarding the physical and chemical properties of lysozyme that support a major role for this protein in host defense, but the biological function of lysozyme in protecting the lower respiratory tract from infection in vivo has not been defined. In this issue of the Journal (pp. 454–458), Markart and colleagues report novel observations that advance our understanding of the functional activities of lysozyme in the antibacterial defenses of the murine lower respiratory tract (6). These investigators used genetically modified mice that over- or under-express lysozyme to demonstrate that this protein has important roles in maintaining the sterility of the lower respiratory tract and in host defense against bacterial pneumonia. First, Markart and coworkers found that the lungs of mice with targeted deletions of lysozyme M, the major form of lysozyme found in the murine respiratory tract, were colonized consistently with lactobacilli, in contrast to the sterile lungs of wild-type control mice. The location of the lactobacilli in the lungs of lysozyme-deficient animals was not defined, and no inflammatory response was evident. This simple observation, however, provides compelling confirmation of what has long been suspected: that the presence of lysozyme helps to prevent colonization of the lower respiratory tract with bacteria. Second, Markart and colleagues found that over- or under-expression of lysozyme influenced resistance to intratracheal challenge with Klebsiella pneumoniae. Transgenic mice, in which rat lysozyme was expressed in the distal airspaces under the control of the surfactant protein C promoter, exhibited augmented bacterial clearance and improved survival in comparison with wild-type controls. The transgenic mice have high levels of lysozyme in bronchoalveolar lavage fluid and have been reported previously by this research group to be resistant to pulmonary infection with Group B streptococci or Pseudomonas aeruginosa (7). In contrast, mice deficient in lysozyme M demonstrated impaired bacterial clearance, persistent lobar consolidation, and increased mortality from K. pneumonia in comparison with controls. Whether lysozyme is exerting a direct antimicrobial effect or modulating the inflammatory response in this model is not clear. These data, however, provide complementary evidence that lysozyme has an important role in host defense against lobar pneumonia. The implications of these observations for human disease are limited by the familiar hazards of comparing mice and men. For one thing, mice have two forms of lysozyme, whereas humans have but one. Lysozyme M is the major form expressed in murine epithelial cells and leukocytes, and lysozyme P is normally limited to the Paneth cells of the small intestine (8, 9). Curiously, lysozyme M–deficient mice express lysozyme P in alveolar macrophages (9). As a result, the lysozyme activity in the lungs of knockout animals was not completely abolished. Furthermore, there are interspecies differences in the antimicrobial spectra of lysozymes (1, 3), and it is not clear that the activity of human lysozyme is comparable to the activity of murine lysozyme against the pathogens tested. More importantly, there are significant differences between humans and rodents in the spatial distribution of lysozyme synthesis in the lower respiratory tract. In humans, lysozyme is secreted predominantly by the serous cells of submucosal glands in the conducting airways and, to a lesser extent, by airway epithelial cells and alveolar macrophages (10–12). In contrast, type II pneumocytes are the major sites of lysozyme synthesis in rodent lungs (7, 11). Thus, lysozyme may have a more important role in antibacterial defense of the distal airspaces in mice than in humans. Despite these limitations, further studies in the murine model may help answer important questions regarding the antimicrobial spectrum, site of activity, and mechanism of action of lysozyme in vivo. Whether or not human lysozyme has a native role in defending the lungs from infection, the studies by Markart and colleagues support an effort to harness the therapeutic potential of lysozyme and other antimicrobial proteins. In an era of increasing antibiotic resistance, new options are needed. FOOTNOTES Conflict of Interest Statement: S.J.S. has no declared conflict of interest. REFERENCES
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