Novel Nonantibiotic Therapies for Pneumonia * : Cytokines and Host Defense

Steve Nelson Chest 2001;119;419S-425S DOI 10.1378/chest.119.2_suppl.419S The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/119/2_suppl/419S.full.html

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2001by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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Novel Nonantibiotic Therapies for Pneumonia*

Cytokines and Host Defense
Steve Nelson, MD, FCCP

Effective host defense against bacterial infection is dependent on the activation and recruitment of phagocytic cells. The initiation, maintenance, and resolution of this inflammatory response in the setting of bacterial pneumonia is dependent on the expression of cytokines. As the complexities of the host-pathogen interaction are further dissected and unraveled, immunologic manipulation of cytokine expression will likely become an important adjuvant therapy in the treatment of serious lung infections. (CHEST 2001; 119:419S 425S)
Key words: cytokines; granulocyte colony-stimulating factor; inflammatory response; interleukins; pneumonia; tumor necrosis factor Abbreviations: CAP community-acquired pneumonia; G-CSF granulocyte colony-stimulating factor; IFNinterferon ; IL interleukin; LPS lipopolysaccharide; PMN polymorphonuclear leukocyte; TNF tumor necrosis factor

epithelial surface area of T he lung isinthe largestwith the external environthe body contact

ment. As normal respiration occurs, the upper and lower airways are repeatedly exposed to a multitude of airborne particles and microorganisms. Since these agents are frequently deposited on the surface of the respiratory tract, an elaborate system of defense mechanisms maintains the sterility of the lung. The primary function of these innate defenses is the elimination of bacterial organisms from the alveolus. A dual phagocytic system involving both alveolar macrophages and polymorphonuclear leukocytes (PMNs) mediates early bacterial clearance (Fig 1).1 The recruitment and activation of inflammatory cells at a site of infection involve the orchestrated expression of leukocyte and vascular adhesion molecules as well as the establishment of chemotactic gradients via the generation of chemokines and cytokines. Alveolar macrophages are the resident phagocytic cells in the lung, and they constitute the first line of defense against infectious agents that reach the gas-exchanging airways.2,3 Alveolar macrophages are avidly phagocytic and readily kill ingested organisms.

*From the Louisiana State University Health Sciences Center, Department of Medicine, Section of Pulmonary/Critical Care Medicine, New Orleans, LA. Correspondence to: Steve Nelson, MD, FCCP, Louisiana State University Health Sciences Center, Department of Medicine, Section of Pulmonary/Critical Care Medicine, 1901 Perdido St, Suite 3205, New Orleans, LA 70112; e-mail: snelso1@lsuhsc.edu

In addition to their phagocytic capabilities, they play a prominent role in orchestrating inflammatory and immune responses.4 These cells respond to the usual daily challenges of bacteria entering the terminal airways and are capable of initiating an inflammatory reaction if the microbial challenge is either too large or too virulent to be contained by the macrophages alone. Under these conditions, the alveolar macrophages initiate an inflammatory response that recruits large numbers of PMNs into the alveolar spaces from the marginated pool of PMNs in the pulmonary vasculature. Substances capable of eliciting the immigration of PMNs into the airways include complement components, arachidonic acid metabolites such as leukotriene B4, and chemotactic peptides such as interleukin (IL)-8 and related chemokines.4,5 Clearly, the cellular components of the innate immune responsethe alveolar macrophage and the neutrophilneed to communicate with each other if an effective host defense is to be mounted. Mechanisms are needed not only to initiate this response, but also to localize, reinforce, and ultimately resolve it. One of the essential components of the immune system that plays a critical role in these processes are the cytokines.4,5 Cytokines are produced by a wide variety of cells in the body, play an important role in many physiologic responses, are involved in the pathophysiology of an extensive range of diseases, and have therapeutic potential. Cytokines that have been shown to fulfill an important role in the innate
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illustrated by TNF. Although initially portrayed as the key mediator in the pathogenesis of septic shock,7 TNF is now recognized as a pivotal part of the hosts response to a broad spectrum of infectious diseases. TNF Named for its ability to trigger the necrosis and involution of certain tumors, TNF is now recognized as a central mediator of the hosts response to infection.8,9 It is rapidly produced following either antigen-specific or nonspecific stimulation and has, therefore, been designated an early response, or alarm, cytokine. Lipopolysaccharide (LPS) is the best studied and most potent stimulus for TNF production. In Gram-negative bacteria, LPS is the major proinflammatory component of the cell walls, and the study of LPS-induced TNF expression by alveolar macrophages is, accordingly, very relevant to the role of TNF in the host defense response during Gram-negative pneumonia. In one of our earlier investigations,10 we determined the effects of LPS on TNF activity and the pulmonary inflammatory response in animals challenged with either IV or intratracheal LPS. In the unchallenged lung, BAL fluid contains no measurable TNF, and the cell population is composed almost exclusively of alveolar macrophages. Following the intratracheal administration of LPS, TNF rapidly rises within the BAL fluid, and a neutrophilic alveolitis develops within the lower respiratory tract. These data suggest a role for TNF as a proximal factor in eliciting the recruitment of PMNs into the lung. This is supported by studies of the neutralization of LPS-induced increases in BAL fluid TNF by either an anti-TNF antibody or a replication-deficient adenovirus encoding a soluble TNF receptor. Both of these anti-TNF molecules suppress PMN influx into the lung.11,12 Most importantly, these studies show that LPS-induced TNF is largely confined to the LPS-challenged compartment. When LPS was administered IV, eliciting a large serum TNF response, TNF was not detected in the BAL fluid. Similarly, intratracheal LPS-induced increases in BAL fluid TNF did not result in an increase in serum TNF. Boujoukos and colleagues13 extended these observations to human volunteers administered IV LPS. In these normal subjects, despite high levels of circulating cytokines following systemic LPS administration, there was no significant increase in BAL fluid levels of TNF, IL-1, IL-6, or IL-8. Dehoux and colleagues14 studied lung and serum cytokine levels in 15 patients with unilateral community-acquired pneumonia (CAP). They too found that the inflammatory response was compartmentalHospital-Acquired Infections: Realities of Risks and Resistance

Figure 1. When bacteria (B) succeed in evading mechanical and ciliary removal and pass through the upper respiratory tract (URT) into the alveolus, they may encounter surfactants and/or antibodies secreted by B-lymphocytes (B LYM), and complement proteins that prepare them for phagocytosis by alveolar macrophages (AM). Attachment of the bacteria to the alveolar macrophage surface membrane is achieved through specialized cell receptors and can be facilitated by antibodies possessing specific opsonizing potential. Complement components can assist with such attachment. At least two additional mechanisms can be activated to enhance killing and clearance of the microbe. The first of these involves alveolar macrophages and their ability to liberate chemotactic factors that attract nearby PMNs and initiate an inflammatory response. The second mechanism occurs when the bacteria trigger T-lymphocytes (T LYM) to release effector substances (cytokines) that may activate or stimulate the phagocytic and bactericidal capacity of alveolar macrophages. Adapted from Reynolds,1 with permission.

immunity of the lung include tumor necrosis factor (TNF), IL-10, IL-12, the chemokines, interferon (IFN- ), and granulocyte colony-stimulating factor (G-CSF). Cytokines and Host Defense While studies have implicated certain cytokines in the pathogenesis of organ injury and death from severe infections, it is important to emphasize that cytokines should be viewed in context.6 The role of a cytokine in either maintaining immune homeostasis or contributing to the pathophysiology of a disease is profoundly influenced by numerous host and local factors. The importance of this concept is clearly
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ized within the infected human lung and was limited to the site of the infection, with localized production of TNF, IL-1, and IL-6. IL-8 While these proinflammatory mediators are not thought to have direct chemoattractant activity, both TNF and IL-1 are potent inducers of IL-8 production by several cell types, including alveolar macrophages, type II epithelial cells, and lung fibroblasts.15 Among this family of chemotactic cytokines, or chemokines, IL-8 has been identified as the major chemotactic factor for PMN in the lung. Boutten and colleagues16 measured serum and BAL fluid IL-8, as well as the number of PMNs in the BAL fluid, in 17 patients with unilateral CAP. IL-8 was found to be elevated in the BAL fluid but not in the serum, and the BAL fluid IL-8 concentrations correlated positively with the numbers of PMN in the BAL fluid. In a model of Klebsiella pneumoniae, Greenberger and colleagues17 showed that in vivo neutralization of macrophage inflammatory protein 2, the functional murine homolog of IL-8, resulted in a 60% reduction in PMN influx, a fourfold increase in the numbers of viable bacteria recovered from the lungs, and early dissemination of K pneumoniae to both the blood and the liver. This selective increase in proinflammatory cytokines may be a critical factor in compartmentalizing the host inflammatory response within a specific tissue site in an attempt to maintain homeostasis. Clearly, it would not be advantageous to the patient infected with pneumonia to activate a generalized systemic response to an initially localized insult. Furthermore, these data suggest that specific mechanisms exist to insulate the lower respiratory tract from the effects of systemic endotoxin and high circulating levels of cytokines. However, in pathologic states, certain cytokines may circulate to act beyond the organ of origin. Therefore, the local production of cytokines is a normal part of the host response to a bacterial infection, and the presence of cytokines under these conditions does not equate with tissue injury or organ failure. If cytokines are important mediators in pulmonary host defense, then an impaired cytokine response should be associated with an increased susceptibility to infections. Neutralization of the TNF response has been shown to impair pulmonary host defenses against a wide range of other pathogens, including Pseudomonas aeruginosa, Legionella pneumophila, K pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis.4,11,12,18 22 It is now widely recognized that TNF is a pivotal

mediator in determining the outcome of a broad array of infectious diseases in the host. Its potential role in immunotherapy would be obvious, except that systemic administration of this proinflammatory cytokine is associated with significant toxicity and poor penetration into the lung. An alternative approach to the direct instillation of TNF into the lung is to prime alveolar macrophages with IFN- , so that they secrete greater amounts of TNF and other mediators in response to an infectious stimulus. IFN- is a cytokine produced by T cells and natural killer cells that is instrumental in cell-mediated immunity and has been shown to enhance several macrophage effector cell functions, including the respiratory burst, macrophage-derived TNF release, and antimicrobial activity.23 IFN- , like TNF, appears to be largely confined to the compartment in which it is endogenously released or experimentally administered.24 In a recent study by Maus and colleagues,25 alveolar macrophages obtained by BAL from patients with severe CAP showed a significantly reduced TNF response to LPS stimulation in vitro. Stimulation of alveolar macrophages from these patients with LPS plus IFN- augmented the TNF response to near-normal levels. Similar findings have been reported in patients with sepsis.26 Whether these findings are relevant for therapeutic strategies to overcome states of impaired host defense in patients with pneumonia awaits further investigation. IL-10 IL-10 is a cytokine that was first recognized for its role in promoting Th2-type immune responses through the inhibition of cell-mediated (Th1) immune responses. It is now clear that IL-10 is also important in the innate immune response to bacterial pathogens. This anti-inflammatory cytokine downregulates the production of TNF, IFN, and certain chemokines. van der Poll and colleagues27 showed that intranasal administration of S pneumoniae results in a marked increase in IL-10 in the lungs of normal mice, and, as has been shown for other cytokines, this response is largely compartmentalized. In this model, intrapulmonary administration of IL-10 2 h prior to the S pneumoniae challenge reduced the lung TNF and IFN- responses. These animals experienced higher lung and blood bacterial counts and increased early mortality. Not surprisingly, treatment of mice with anti-IL-10 antibody prior to the pneumococcal lung challenge was associated with a significant increase in lung TNF, a sixfold decrease in lung bacterial count, and improved survival. Greenberger and colleagues28 similarly reported that administration of a polyclonal
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anti-IL-10 antiserum in a murine model of K pneumoniae resulted in improved host defense and prolonged survival. IL-12 IL-12 is a heterodimeric protein consisting of two subunits (p35 and p40) and was initially recognized for its ability to promote Th1-type immune responses. Numerous studies have shown that IL-12 can enhance cell-mediated host resistance to a wide range of intracellular pathogens.29 Utilizing immunohistochemical techniques in animals infected with K pneumoniae, researchers have found that IL-12 production appears to be localized primarily to alveolar macrophages, pulmonary epithelial cells, and PMN. Greenberger and colleagues30 studied the role of IL-12 in innate immunity in mice intratracheally challenged with K pneumoniae. This bacterial challenge resulted in a time-dependent increase in IL-12 messenger RNA and protein in the lung. Passive immunization with anti-IL12 serum at the time of the bacterial challenge suppressed the bactericidal activity of the lung and decreased survival. Intratracheal administration of a nonreplicating adenoviral vector containing a cytomegalovirus promoter and complementary DNAs coding for both the p35 and p40 subunits of IL-12 improved survival. These survival benefits were reduced if either endogenous TNF or IFN- was neutralized in vivo in these animals transfected with this adenoviral vector. G-CSF For more than a century, physicians have recognized the relationship of the WBC count to the occurrence, severity, and outcome of many infectious diseases. Leukocytosis and neutrophilia were noted as frequent markers of infectious processes in Oslers first textbook of medicine.31 However, the physiologic principles underlying these responses were poorly understood. Colony-stimulating factors are a family of acidic glycoproteins that are required for the proliferation and differentiation of hematopoietic progenitor cells. Of this cytokine family, which includes granulocyte macrophage colonystimulating factor, macrophage colony-stimulating factor, IL-3, and G-CSF, it is G-CSF that plays an important role in maintaining the normal blood PMN count and enhancing the functional properties of PMN, including chemotaxis, phagocytosis, and bactericidal activity (reviewed in Dale et al32 in 1995). Examination of the lung may be particularly useful in determining the role of endogenous G-CSF in infectious states. Mononuclear phagocytes, including alveolar macrophages, are known to produce G-CSF when stimulated by bacterial products or cytokines.
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Tazi and colleagues33 reported that alveolar macrophages recovered from patients with pneumonia produce G-CSF spontaneously, whereas alveolar macrophages from healthy control subjects produce G-CSF only after LPS stimulation. Furthermore, we have also shown that G-CSF, in contrast to TNF and other cytokines, is not compartmentalized, and intrapulmonary instillation of G-CSF results in a significant increase in the number of circulating PMNs.34 We hypothesize that one of the major roles of mononuclear phagocytes (such as the alveolar macrophage) during infection is the local production of cytokines (such as TNF and IL-1), which subsequently induce the alveolar macrophage population to produce G-CSF. Under this hypothesis, G-CSF acts locally to activate and recruit PMNs into the infected lung and functions systemically to stimulate the formation of additional PMNs, thus reinforcing the hosts response until the infection is resolved (Fig 2). The ability of G-CSF to selectively increase both the number and function of PMNs makes G-CSF an attractive candidate for biological immunotherapy in patients with serious infections. Numerous preclinical investigations in a wide variety of infection models have shown that administration of G-CSF enhances host defenses.32 In several models of severe pneumonia, G-CSF improves survival. Splenectomy is a known risk factor for increased morbidity and mortality resulting

Figure 2. Pulmonary host defense against bacterial infection may involve the effects of G-CSF; M macrophage. From Nelson and Bagby,34 with permission.
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from pneumococcal pneumonia. In a murine model, G-CSF administered from 24 h before challenge to 3 days after the challenge improved survival among splenectomized mice exposed to an aerosol challenge with S pneumoniae.35 To study the effect of G-CSF in a rabbit model of Gram-negative pneumonia and sepsis, Smith and colleagues36 inoculated rabbits transtracheally with Pasteurella multocida and treated them 24 h later with penicillin G and either G-CSF or placebo once daily for up to 5 days. All rabbits underwent careful histologic examination at the time of septic death or when killed on day 6. In this study, sepsis-induced leukopenia was a predictor of significantly improved survival with G-CSF therapy (57%, vs 39% in control animals). Interestingly, the majority of the survival benefit occurred within the first 24 h of G-CSF treatment, which was prior to the onset of G-CSF-induced neutrophilia. Histologic examination of these animals did not demonstrate evidence of organ toxicity related to G-CSF therapy. Based on the favorable results obtained from preclinical studies, clinical trials have begun using G-CSF as an adjuvant to antibiotics in the treatment of patients with pneumonia. A phase III, doubleblind, placebo-controlled trial of recombinant human G-CSF for the treatment of hospitalized patients with CAP has recently been concluded.37 This was a multicenter trial involving 756 patients enrolled in 71 centers in the United States, Canada, and Australia. Participants in this study were randomized to receive 300 g/d G-CSF (380 patients) or placebo (376 patients) in addition to conventional antibiotic therapy. Treatment duration was for up to 10 days, and the length of the study observation period was 28 days or until death. The primary objectives of the study were to determine safety and the effect of G-CSF on the time to resolution of morbidity, which was defined as an index of several clinical variables that are useful in determining whether a patient with pneumonia is benefiting from therapy.38 Mortality was low (6%) in this study, and length of stay was only 7 days. Both variables were unaffected by G-CSF treatment. Similarly, the time to resolution of morbidity was 4 days in each treatment group. Treatment with G-CSF was safe and well tolerated. In the intent-to-treat analysis, G-CSF increased blood neutrophil levels threefold, significantly accelerated radiographic resolution of pneumonia, and reduced serious complications. Post hoc analyses showed that these benefits were more pronounced in patients with multilobar pneumonia. In this study, there were 261 patients with multilobar pneumonia, and 28% of these patients were admitted to an ICU at study entry. Based on the favorable trends seen in these stud-

ies, additional trials in patients with multilobar pneumonia and in patients with severe pneumonia and sepsis were initiated and recently completed. The primary end point in the study of G-CSF in patients with multilobar pneumonia was a reduction in the development of organ dysfunction (ARDS, disseminated intravascular coagulation, acute renal failure, shock). A reduction in mortality was the primary efficacy end point in the pneumonia/sepsis trial. Although analyses of these studies are ongoing, the primary end point in both trials was not significantly different for the G-CSF and placebo treatment groups. What mechanisms are responsible for the beneficial effects of G-CSF therapy that have been observed in these nonneutropenic infected hosts? Are these benefits related more to G-CSF-induced neutrophilia than to enhanced neutrophil function? Several possibilities have been proposed. One of these that we find particularly intriguing is the effect of G-CSF on neutrophil-antibiotic interactions. Certain antibiotics are known to concentrate in neutrophils, and since G-CSF enhances many of the functions of these cells, we hypothesized that G-CSF might increase the uptake of certain antibiotics into this cell. Furthermore, since G-CSF increases the number of cells responding to an infection, neutrophil-mediated transport of antibiotics to the site of infection might also be increased. These effects may be particularly important in parts of the body where delivery of antibiotics is difficult and/or in the treatment of pathogens that are relatively resistant to treatment. To test this hypothesis, we incubated human neutrophils with G-CSF and ciprofloxacin.39 It is known that concentrations of ciprofloxacin within PMNs are normally three to four times greater than extracellular concentrations of the drug. In these studies, G-CSF increased the intracellularto-extracellular concentration of ciprofloxacin approximately 10-fold. Yasuda and colleagues40 studied the correlation between the number of PMNs in the blood at the time of infection and the therapeutic efficacy of an antibiotic. In these experiments, the therapeutic effect of netilmicin, an aminoglycoside, was not significantly affected by the number of PMNs at the time of infection. In contrast, however, the therapeutic effect of ceftazidime, a -lactam, was strikingly affected by the number of PMNs in the blood at the time of infection. A 75% decrease in number of blood PMNs at the time of infection resulted in a 99% decrease in therapeutic efficacy of ceftazidime, while a 10-fold increase in PMNs resulted in a 10-fold increase in the anti-infection activity of ceftazidime.
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Conclusion Because of their role in mediating critical aspects of innate immunity, synthetic cytokines have a great potential for reducing the morbidity and mortality caused by bacterial infections of the lower respiratory tract and have begun to find their way into clinical trials. Manipulation of innate immunity may serve as an important adjuvant therapy in the treatment of both immunocompromised and immunocompetent patients with severe lung infections. As the complexities of the host-pathogen interaction are further dissected and unraveled, it is likely that the therapeutic benefits from these approaches will be fully realized. References
1 Reynolds HY. Normal and defective respiratory host defenses. In: Pennington JE, ed. Respiratory infections: diagnosis and management. 2nd ed. New York, NY: Raven Press, 1988; 133 2 Fels AO, Cohn ZA. The alveolar macrophage. J Appl Physiol 1986; 60:353369 3 Sibille Y, Reynolds HY. Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am Rev Respir Dis 1990; 141:471501 4 Nelson S, Mason CM, Kolls J, et al. Pathophysiology of pneumonia. Clin Chest Med 1995; 16:112 5 Standiford TJ, Kunkel SL, Greenberger MJ, et al. Expression and regulation of chemokines in bacterial pneumonia. J Leukoc Biol 1996; 59:24 28 6 Nathan C, Sporn M. Cytokines in context. J Cell Biol 1991; 113:981986 7 Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470 474 8 Carswell EA, Old LJ, Kassel RL, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975; 72:3666 3670 9 Old LJ. Tumor necrosis factor (TNF). Science 1985; 230: 630 632 10 Nelson S, Bagby GJ, Bainton BG, et al. Compartmentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response. J Infect Dis 1989; 159:189 194 11 Kolls JK, Lei D, Nelson S, et al. Adenovirus-mediated blockade of tumor necrosis factor in mice protects against endotoxic shock yet impairs pulmonary host defense. J Infect Dis 1995; 171:570 575 12 Nelson S, Bagby G, Summer W. Anti-tumor necrosis factorantibody suppresses pulmonary antibacterial defenses [abstract]. Am Rev Respir Dis 1991; 143S:A393 13 Boujoukos AJ, Martich GD, Supinski E, et al. Compartmentalization of the acute cytokine response in humans after intravenous endotoxin administration. J Appl Physiol 1993; 74:30273033 14 Dehoux MS, Boutten A, Ostinelli J, et al. Compartmentalized cytokine production within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 1994; 150:710 716 15 Kunkel SL, Standiford T, Kasahara K, et al. Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung. Exp Lung Res 1991; 17:1723 16 Boutten A, Dehoux MS, Seta N, et al. Compartmentalized
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17

18

19

20

21

22

23

24

25

26

27

28

29 30

31 32

33

34

35

IL-8 and elastase release within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 1996; 153:336 342 Greenberger MJ, Streiter RM, Kunkel SL, et al. Neutralization of macrophage inflammatory protein-2 attenuates neutrophil recruitment and bacterial clearance in murine Klebsiella pneumonia. J Infect Dis 1996; 173:159 165 Blanchard DK, Djeu JY, Klein TW, et al. Protective effects of tumor necrosis factor in experimental Legionella pneumophila infections of mice via activation of PMN function. J Leukoc Biol 1988; 43:429 435 Laichalk LL, Kunkel SL, Strieter RM, et al. Tumor necrosis factor mediates lung antibacterial host defense in murine Klebsiella pneumonia. Infect Immun 1996; 64:52115218 Skerrett SJ, Bagby GJ, Schmidt RA, et al. Antibody-mediated depletion of tumor necrosis factor- impairs pulmonary host defenses to Legionella pneumophila. J Infect Dis 1997; 176:1019 1028 van der Poll T, Keogh CV, Buurman WA, et al. Passive immunization against tumor necrosis factor- impairs host defense during pneumococcal pneumonia in mice. Am J Respir Crit Care Med 1997; 155:603 608 Flynn JL, Goldstein MM, Chan J, et al. Tumor necrosis factor- is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2:561572 Jensen WA, Rose RM, Wasserman AS, et al. In vitro activation of the antibacterial activity of human pulmonary macrophages by recombinant interferon. J Infect Dis 1987; 155:574 577 Jaffe HA, Buhl R, Mastrangeli A, et al. Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon- to the human lung. J Clin Invest 1991; 88:279 302 Maus U, Rosseau S, Knies U, et al. Expression of proinflammatory cytokines by flow-sorted alveolar macrophages in severe pneumonia. Eur Respir J 1998; 11:534 541 Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN- treatment. Nat Med 1997; 3:678 681 van der Poll T, Marchant A, Keogh CV, et al. Interleukin-10 impairs host defense in murine pneumococcal pneumonia. J Infect Dis 1996; 174:994 1000 Greenberger MJ, Strieter RM, Kunkel SL, et al. Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. J Immunol 1995; 155:722729 Brunda MJ. Interleukin-12. J Leukoc Biol 1994; 55:280 288 Greenberger MJ, Kunkel SL, Strieter RM, et al. IL-2 gene therapy protects mice in lethal Klebsiella pneumonia. J Immunol 1996; 157:3006 3012 Osler W. The principles and practice of medicine. New York, NY: D. Appleton, 1892 Dale DC, Liles WC, Summer WR, et al. Granulocyte colonystimulating factor: role and relationships in infectious diseases. J Infect Dis 1995; 172:10611075 Tazi A, Nioche S, Chastre J, et al. Spontaneous release of granulocyte colony-stimulating factor (G-CSF) by alveolar macrophages in the course of bacterial pneumonia and sarcoidosis: endotoxin-dependent and endotoxin-independent G-CSF release by cells recovered by bronchoalveolar lavage. Am J Respir Cell Mol Biol 1991; 4:140 147 Nelson S, Bagby GJ. Granulocyte colony-stimulating factor and modulation of inflammatory cells in sepsis. Clin Chest Med 1996; 17:319 332 Hebert JC, OReilly M, Gamelli RL. Protective effect of
Hospital-Acquired Infections: Realities of Risks and Resistance

Downloaded from chestjournal.chestpubs.org by guest on March 15, 2012 2001 American College of Chest Physicians

recombinant human granulocyte colony-stimulating factor against pneumococcal infections in splenectomized mice. Arch Surg 1990; 125:10751078 36 Smith WS, Sumnicht GE, Sharpe RW, et al. Granulocyte colony-stimulating factor versus placebo in addition to penicillin G in a randomized blinded study of Gram-negative pneumonia sepsis: analysis of survival and multisystem organ failure. Blood 1995; 86:13011309 37 Nelson S, Farkas S, Fotheringham N, et al. Filgrastim in the treatment of hospitalized patients with community acquired pneumonia (CAP) [abstract]. Am J Respir Crit Care Med 1996; 153S:A535

38 Daifuku R, Movahhed H, Fotheringham N, et al. Time to resolution of morbidity: an endpoint for assessing the clinical cure of community-acquired pneumonia. Respir Med 1996; 90:587592 39 McKenna PJ, Nelson S, Andresen J. Filgrastim (rhuG-CSF) enhances ciprofloxacin uptake and bactericidal activity of human neutrophils in vitro [abstract]. Am J Respir Crit Care Med 1996; 153S:A535. 40 Yasuda H, Ajiki Y, Shimozato T, et al. Therapeutic efficacy of granulocyte colony-stimulating factor alone and in combination with antibiotics against Pseudomonas aeruginosa infection in mice. Infect Immun 1990; 58:25022509

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Novel Nonantibiotic Therapies for Pneumonia* : Cytokines and Host Defense Steve Nelson Chest 2001;119; 419S-425S DOI 10.1378/chest.119.2_suppl.419S This information is current as of March 15, 2012
Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/119/2_suppl/419S.full.html References This article cites 36 articles, 26 of which can be accessed free at: http://chestjournal.chestpubs.org/content/119/2_suppl/419S.full.html#ref-list-1 Cited Bys This article has been cited by 4 HighWire-hosted articles: http://chestjournal.chestpubs.org/content/119/2_suppl/419S.full.html#related-urls Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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