Preface [Hot Topic: Novel Immunomodulatory Effects of Macrolides in Inflammatory Lung Disease (Executive Editors: F. Martinez and T.J. Standiford)]

Ever since the isolation of erythromycin from Streptomyces erythreus more than 50 years ago, macrolide antibiotics have assumed a prominent position in our pharmacological armamentarium against a variety of microbial pathogens. The broad spectrum activity and intracellular accumulation of this class of antibiotics account for the substantial clinical efficacy of macrolides against both extracellular and intracellular pathogens, particularly in the setting of infection of the upper and lower respiratory tract. More recently, 14 and 15 membered ring macrolides have been found to modulate inflammatory responses to bacterial challenge in a manner that is independent of effects on bacterial viability. For instance, macrolide antibiotics are generally unable to kill certain gram-negative bacteria such as Pseudomonas aeruginosa at physiologically achievable concentrations in-vivo. However, these agents can substantially alter the virulence of P. aeruginosa by attenuating the expression of key virulence factors that are required for bacterial persistence and invasiveness. Moreover, specific members of the macrolide family have been discovered that exert important immunomodulatory effects on host inflammatory responses. These immunomodulatory effects, which appear to be unique to the macrolide family of antibiotics, were first recognized by Professor Kudoh in Tokyo, Japan, who made the astute observation that the long term administration of erythromycin to a patient with diffuse panbronchiolitis (DPB) resulted in a striking reversal of the usually progressive nature of this disease. In fact, the use of erythromycin and other 14 and 15 membered ring macrolides for the treatment of advanced DPB has resulted in a dramatic increase in the 10-year survival of this disease from less than 15% to nearly 90%. Clinical successes in the treatment of DPB have lead to trials assessing the efficacy of macrolides in other inflammatory airways diseases, including asthma and cystic fibrosis. Importantly, several macrolides have been proven in single center and multicenter controlled trials to reduce symptoms and improve pulmonary function in patients with cystic fibrosis. These encouraging results have ignited the performance of a large body of in-vitro and in-vivo studies to determine the mechanism(s) by which this family of antibiotics modulates the immune response. This issue will focus on these novel immunomodulatory properties of macrolides, including effects on both bacterial responses and host immune / inflammatory responses. In Chapter 1, Drs. Jain and Danziger [1] have nicely outlined the unique pharmacokinetic and pharmacodynamic aspects of macrolide antibiotics, with a particular emphasis on features that contribute to antibacterial and immunomodulatory effects in the lung. Dr. Tateda and colleagues [2] provide an insightful overview of non-bactericidal effects of macrolides on P. aeruginosa, including the influence of these antibiotics on bacterial quorum-sensing systems and other virulence factors. Dr. Labros [3] has provided a comprehensive review of macrolide effects in pulmonary and non-pulmonary inflammatory disease states, with a focus on immunomodulation of leukocyte effector cell function in these diseases. In Chapter 4, Drs. Tsai and Standiford [4] discuss the influence of various macrolides on the immune / inflammatory responses of lung cells both in-vitro and in animal models of lung disease. Finally, Drs. Martinez and Simon [5] present an exciting review of macrolide effects in inflammatory sinopulmonary disease, highlighting the clinical successes realized in DPB and cystic fibrosis. Given the pace of discovery in this field, a comprehensive review of immunomodulatory properties of macrolides is indeed timely and of unquestioned clinical relevance. While work performed to date has largely focused on lung-specific effects, it is probable that macrolide immunomodulatory properties are applicable to disease states involving organ systems outside the lung. It is our hope that this review will generate interest in research aimed at further defining mechanisms of macrolide immunomodulatory effects, as well as identify new therapeutic applications of macrolides in the treatment of acute and chronic disease.