This action might not be possible to undo. Are you sure you want to continue?
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
Downloaded from chestjournal.chestpubs.org by guest on March 15, 2012 © 2001 American College of Chest Physicians
New Orleans. 2001 SUPPLEMENT 419S Downloaded from chestjournal. As the complexities of the host-pathogen interaction are further dissected and unraveled. As normal respiration occurs. are involved in the pathophysiology of an extensive range of diseases. Alveolar macrophages are the resident phagocytic cells in the lung. they play a prominent role in orchestrating inflammatory and immune responses.edu In addition to their phagocytic capabilities. G-CSF granulocyte colony-stimulating factor.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. Department of Medicine. Correspondence to: Steve Nelson. MD. The primary function of these innate defenses is the elimination of bacterial organisms from the alveolus. the cellular components of the innate immune response—the alveolar macrophage and the neutrophil—need to communicate with each other if an effective host defense is to be mounted. Since these agents are frequently deposited on the surface of the respiratory tract. The initiation. PMN polymorphonuclear leukocyte. interleukins. an elaborate system of defense mechanisms maintains the sterility of the lung.4. Department of Medicine. and they constitute the first line of defense against infectious agents that reach the gas-exchanging airways.5 Cytokines are produced by a wide variety of cells in the body. TNF tumor necrosis factor epithelial surface area of T he lung isinthe largestwith the external environthe body contact ment. and have therapeutic potential. pneumonia. Substances capable of eliciting the immigration of PMNs into the airways include complement components. the upper and lower airways are repeatedly exposed to a multitude of airborne particles and microorganisms. IFNinterferon . IL interleukin. 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. New Orleans. One of the essential components of the immune system that plays a critical role in these processes are the cytokines. but also to localize. LA. FCCP Effective host defense against bacterial infection is dependent on the activation and recruitment of phagocytic cells. arachidonic acid metabolites such as leukotriene B4.org by guest on March 15. (CHEST 2001. reinforce. 1901 Perdido St. immunologic manipulation of cytokine expression will likely become an important adjuvant therapy in the treatment of serious lung infections. Section of Pulmonary/Critical Care Medicine. Section of Pulmonary/Critical Care Medicine.4.1 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. maintenance. LPS lipopolysaccharide. Cytokines that have been shown to fulfill an important role in the innate CHEST / 119 / 2 / FEBRUARY. A dual phagocytic system involving both alveolar macrophages and polymorphonuclear leukocytes (PMNs) mediates early bacterial clearance (Fig 1). inflammatory response. LA 70112. and chemotactic peptides such as interleukin (IL)-8 and related chemokines. Mechanisms are needed not only to initiate this response. *From the Louisiana State University Health Sciences Center. play an important role in many physiologic responses. 119:419S– 425S) Key words: cytokines.Novel Nonantibiotic Therapies for Pneumonia* Cytokines and Host Defense Steve Nelson. e-mail: snelso1@lsuhsc. MD. 2012 © 2001 American College of Chest Physicians . granulocyte colony-stimulating factor. FCCP. Louisiana State University Health Sciences Center. and ultimately resolve it.5 Clearly.2.chestpubs.3 Alveolar macrophages are avidly phagocytic and readily kill ingested organisms. and resolution of this inflammatory response in the setting of bacterial pneumonia is dependent on the expression of cytokines. Under these conditions. tumor necrosis factor Abbreviations: CAP community-acquired pneumonia. Suite 3205.
intratracheal LPS-induced increases in BAL fluid TNF did not result in an increase in serum TNF.org by guest on March 15.7 TNF is now recognized as a pivotal part of the host’s response to a broad spectrum of infectious diseases. In Gram-negative bacteria. there was no significant increase in BAL fluid levels of TNF. the chemokines.).” cytokine. despite high levels of circulating cytokines following systemic LPS administration. 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. In the unchallenged lung.8. Complement components can assist with such attachment. been designated an early response. When LPS was administered IV. it is important to emphasize that cytokines should be viewed in context. IL-10.11. At least two additional mechanisms can be activated to enhance killing and clearance of the microbe. Boujoukos and colleagues13 extended these observations to human volunteers administered IV LPS. Dehoux and colleagues14 studied lung and serum cytokine levels in 15 patients with unilateral community-acquired pneumonia (CAP). TNF is now recognized as a central mediator of the host’s response to infection. eliciting a large serum TNF response. These data suggest a role for TNF as a proximal factor in eliciting the recruitment of PMNs into the lung. and granulocyte colony-stimulating factor (G-CSF). 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. IL-12. Adapted from Reynolds. TNF rapidly rises within the BAL fluid. 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. The importance of this concept is clearly 420S Downloaded from chestjournal. Although initially portrayed as the key mediator in the pathogenesis of septic shock. Both of these anti-TNF molecules suppress PMN influx into the lung.chestpubs. BAL fluid contains no measurable TNF. very relevant to the role of TNF in the host defense response during Gram-negative pneumonia. therefore. In one of our earlier investigations. 2012 © 2001 American College of Chest Physicians . They too found that the inflammatory response was compartmentalHospital-Acquired Infections: Realities of Risks and Resistance Figure 1.10 we determined the effects of LPS on TNF activity and the pulmonary inflammatory response in animals challenged with either IV or intratracheal LPS. Similarly. these studies show that LPS-induced TNF is largely confined to the LPS-challenged compartment. LPS is the major proinflammatory component of the cell walls. and complement proteins that prepare them for phagocytosis by alveolar macrophages (AM). accordingly.9 It is rapidly produced following either antigen-specific or nonspecific stimulation and has. The first of these involves alveolar macrophages and their ability to liberate chemotactic factors that attract nearby PMNs and initiate an inflammatory response. TNF Named for its ability to trigger the necrosis and involution of certain tumors. interferon (IFN.12 Most importantly. and a neutrophilic alveolitis develops within the lower respiratory tract. and the study of LPS-induced TNF expression by alveolar macrophages is. immunity of the lung include tumor necrosis factor (TNF).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. or IL-8. Cytokines and Host Defense While studies have implicated certain cytokines in the pathogenesis of organ injury and death from severe infections. IL-6. When bacteria (B) succeed in evading mechanical and ciliary removal and pass through the upper respiratory tract (URT) into the alveolus. Lipopolysaccharide (LPS) is the best studied and most potent stimulus for TNF production.illustrated by TNF. In these normal subjects.1 with permission. IL-1. or “alarm. TNF was not detected in the BAL fluid. they may encounter surfactants and/or antibodies secreted by B-lymphocytes (B LYM). and the cell population is composed almost exclusively of alveolar macrophages. Following the intratracheal administration of LPS.
K pneumoniae. this response is largely compartmentalized. These animals experienced higher lung and blood bacterial counts and increased early mortality.augmented the TNF response to near-normal levels. with localized production of TNF. it would not be advantageous to the patient infected with pneumonia to activate a generalized systemic response to an initially localized insult. Not surprisingly. and Mycobacterium tuberculosis. 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. Staphylococcus aureus.23 IFN.15 Among this family of chemotactic cytokines.11.org by guest on March 15. including the respiratory burst.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. Greenberger and colleagues28 similarly reported that administration of a polyclonal CHEST / 119 / 2 / FEBRUARY. Neutralization of the TNF response has been shown to impair pulmonary host defenses against a wide range of other pathogens. IL-8 While these proinflammatory mediators are not thought to have direct chemoattractant activity. and the BAL fluid IL-8 concentrations correlated positively with the numbers of PMN in the BAL fluid. Legionella pneumophila. a fourfold increase in the numbers of viable bacteria recovered from the lungs. and IL-6. and certain chemokines. 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. and. including Pseudomonas aeruginosa. 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. If cytokines are important mediators in pulmonary host defense. and the presence of cytokines under these conditions does not equate with tissue injury or organ failure..12. Greenberger and colleagues17 showed that in vivo neutralization of macrophage inflammatory protein 2. appears to be largely confined to the compartment in which it is endogenously released or experimentally administered. IFN. It is now clear that IL-10 is also important in the innate immune response to bacterial pathogens. IL-8 was found to be elevated in the BAL fluid but not in the serum. and antimicrobial activity. 2001 SUPPLEMENT 421S Downloaded from chestjournal. Therefore. as has been shown for other cytokines. including alveolar macrophages. Furthermore. In a model of Klebsiella pneumoniae.chestpubs. then an impaired cytokine response should be associated with an increased susceptibility to infections. or chemokines. IFN. and early dissemination of K pneumoniae to both the blood and the liver. Stimulation of alveolar macrophages from these patients with LPS plus IFN. as well as the number of PMNs in the BAL fluid.ized within the infected human lung and was limited to the site of the infection. and lung fibroblasts. Boutten and colleagues16 measured serum and BAL fluid IL-8.responses.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.4. treatment of mice with anti-IL-10 antibody prior to the pneumococcal lung challenge was associated with a significant increase in lung TNF.24 In a recent study by Maus and colleagues. IL-1. However. Its potential role in immunotherapy would be obvious. An alternative approach to the direct instillation of TNF into the lung is to prime alveolar macrophages with IFN. Streptococcus pneumoniae. the local production of cytokines is a normal part of the host response to a bacterial infection.25 alveolar macrophages obtained by BAL from patients with severe CAP showed a significantly reduced TNF response to LPS stimulation in vitro. both TNF and IL-1 are potent inducers of IL-8 production by several cell types. the functional murine homolog of IL-8. resulted in a 60% reduction in PMN influx.. and improved survival. This anti-inflammatory cytokine downregulates the production of TNF. In this model. IL-8 has been identified as the major chemotactic factor for PMN in the lung. so that they secrete greater amounts of TNF and other mediators in response to an infectious stimulus. except that systemic administration of this proinflammatory cytokine is associated with significant toxicity and poor penetration into the lung. 2012 © 2001 American College of Chest Physicians . certain cytokines may circulate to act beyond the organ of origin. intrapulmonary administration of IL-10 2 h prior to the S pneumoniae challenge reduced the lung TNF and IFN. in pathologic states.26 Whether these findings are relevant for therapeutic strategies to overcome states of impaired host defense in patients with pneumonia awaits further investigation. 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. Similar findings have been reported in patients with sepsis. in 17 patients with unilateral CAP. macrophage-derived TNF release. like TNF. type II epithelial cells. a sixfold decrease in lung bacterial count.
Examination of the lung may be particularly useful in determining the role of endogenous G-CSF in infectious states. 422S Tazi and colleagues33 reported that alveolar macrophages recovered from patients with pneumonia produce G-CSF spontaneously. G-CSF For more than a century. Splenectomy is a known risk factor for increased morbidity and mortality resulting Figure 2. severity.31 However. and outcome of many infectious diseases.chestpubs. it is G-CSF that plays an important role in maintaining the normal blood PMN count and enhancing the functional properties of PMN. we have also shown that G-CSF. and PMN. Mononuclear phagocytes. in contrast to TNF and other cytokines.29 Utilizing immunohistochemical techniques in animals infected with K pneumoniae. G-CSF acts locally to activate and recruit PMNs into the infected lung and functions systemically to stimulate the formation of additional PMNs. including alveolar macrophages. Pulmonary host defense against bacterial infection may involve the effects of G-CSF. which subsequently induce the alveolar macrophage population to produce G-CSF. macrophage colony-stimulating factor. 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. phagocytosis. which includes granulocyte macrophage colonystimulating factor.was neutralized in vivo in these animals transfected with this adenoviral vector.34 with permission. thus reinforcing the host’s response until the infection is resolved (Fig 2). are known to produce G-CSF when stimulated by bacterial products or cytokines.anti-IL-10 antiserum in a murine model of K pneumoniae resulted in improved host defense and prolonged survival. pulmonary epithelial cells. MØ macrophage. the physiologic principles underlying these responses were poorly understood. whereas alveolar macrophages from healthy control subjects produce G-CSF only after LPS stimulation.org by guest on March 15. From Nelson and Bagby.32 In several models of severe pneumonia. Numerous studies have shown that IL-12 can enhance cell-mediated host resistance to a wide range of intracellular pathogens. researchers have found that IL-12 production appears to be localized primarily to alveolar macrophages. Under this hypothesis. 2012 © 2001 American College of Chest Physicians . Leukocytosis and neutrophilia were noted as frequent markers of infectious processes in Osler’s first textbook of medicine. Colony-stimulating factors are a family of acidic glycoproteins that are required for the proliferation and differentiation of hematopoietic progenitor cells. 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. Hospital-Acquired Infections: Realities of Risks and Resistance Downloaded from chestjournal. Numerous preclinical investigations in a wide variety of infection models have shown that administration of G-CSF enhances host defenses. Greenberger and colleagues30 studied the role of IL-12 in innate immunity in mice intratracheally challenged with K pneumoniae. 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. including chemotaxis. and bactericidal activity (reviewed in Dale et al32 in 1995). Furthermore. physicians have recognized the relationship of the WBC count to the occurrence. These survival benefits were reduced if either endogenous TNF or IFN. G-CSF improves survival. is not compartmentalized. IL-3.34 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). Of this cytokine family. and G-CSF. Passive immunization with anti-IL–12 serum at the time of the bacterial challenge suppressed the bactericidal activity of the lung and decreased survival. and intrapulmonary instillation of G-CSF results in a significant increase in the number of circulating PMNs. This bacterial challenge resulted in a time-dependent increase in IL-12 messenger RNA and protein in the lung.
Both variables were unaffected by G-CSF treatment.org by guest on March 15. In this study. In these experiments. Interestingly. CHEST / 119 / 2 / FEBRUARY. vs 39% in control animals). 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. 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. Certain antibiotics are known to concentrate in neutrophils. Treatment with G-CSF was safe and well tolerated. we incubated human neutrophils with G-CSF and ciprofloxacin. while a 10-fold increase in PMNs resulted in a 10-fold increase in the anti-infection activity of ceftazidime. and the length of the study observation period was 28 days or until death. clinical trials have begun using G-CSF as an adjuvant to antibiotics in the treatment of patients with pneumonia. placebo-controlled trial of recombinant human G-CSF for the treatment of hospitalized patients with CAP has recently been concluded. All rabbits underwent careful histologic examination at the time of septic death or when killed on day 6. In contrast.39 It is known that concentrations of ciprofloxacin within PMNs are normally three to four times greater than extracellular concentrations of the drug. G-CSF increased the intracellularto-extracellular concentration of ciprofloxacin approximately 10-fold. the time to resolution of morbidity was 4 days in each treatment group. however.35 To study the effect of G-CSF in a rabbit model of Gram-negative pneumonia and sepsis. In these studies.from pneumococcal pneumonia. was strikingly affected by the number of PMNs in the blood at the time of infection. which was prior to the onset of G-CSF-induced neutrophilia. 2012 © 2001 American College of Chest Physicians . an aminoglycoside. the therapeutic effect of netilmicin. and length of stay was only 7 days. In this study. which was defined as an index of several clinical variables that are useful in determining whether a patient with pneumonia is benefiting from therapy. Based on the favorable results obtained from preclinical studies. significantly accelerated radiographic resolution of pneumonia. sepsis-induced leukopenia was a predictor of significantly improved survival with G-CSF therapy (57%. Based on the favorable trends seen in these stud- ies. acute renal failure. was not significantly affected by the number of PMNs at the time of infection. and reduced serious complications. 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. To test this hypothesis. a -lactam. A 75% decrease in number of blood PMNs at the time of infection resulted in a 99% decrease in therapeutic efficacy of ceftazidime. the primary end point in both trials was not significantly different for the G-CSF and placebo treatment groups. neutrophil-mediated transport of antibiotics to the site of infection might also be increased. there were 261 patients with multilobar pneumonia. we hypothesized that G-CSF might increase the uptake of certain antibiotics into this cell. Although analyses of these studies are ongoing. since G-CSF increases the number of cells responding to an infection. and since G-CSF enhances many of the functions of these cells. A phase III. Similarly.37 This was a multicenter trial involving 756 patients enrolled in 71 centers in the United States. G-CSF increased blood neutrophil levels threefold. Furthermore.38 Mortality was low (6%) in this study. In a murine model. doubleblind. 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. 2001 SUPPLEMENT 423S Downloaded from chestjournal. Histologic examination of these animals did not demonstrate evidence of organ toxicity related to G-CSF therapy. One of these that we find particularly intriguing is the effect of G-CSF on neutrophil-antibiotic interactions. and 28% of these patients were admitted to an ICU at study entry. shock). disseminated intravascular coagulation. Treatment duration was for up to 10 days. A reduction in mortality was the primary efficacy end point in the pneumonia/sepsis trial. 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.chestpubs. 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. and Australia. the therapeutic effect of ceftazidime. Post hoc analyses showed that these benefits were more pronounced in patients with multilobar pneumonia. 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. Canada. additional trials in patients with multilobar pneumonia and in patients with severe pneumonia and sepsis were initiated and recently completed. In the intent-to-treat analysis. the majority of the survival benefit occurred within the first 24 h of G-CSF treatment. The primary objectives of the study were to determine safety and the effect of G-CSF on the time to resolution of morbidity.
Am Rev Respir Dis 1991. New York.chestpubs. et al. Gamelli RL. Knies U. Adenovirus-mediated blockade of tumor necrosis factor in mice protects against endotoxic shock yet impairs pulmonary host defense. 60:353–369 3 Sibille Y. et al. Shock and tissue injury induced by recombinant human cachectin. Old LJ. 176:1019 –1028 van der Poll T. Proc Natl Acad Sci USA 1975. et al. 88:279 –302 Maus U. Strieter RM. 16:1–12 5 Standiford TJ. et al. 234:470 – 474 8 Carswell EA. 55:280 –288 Greenberger MJ. Cytokines in context. Monocyte deactivation ¨ in septic patients: restoration by IFN. Boutten A. Am Rev Respir Dis 1990. Cohn ZA. 64:5211–5218 Skerrett SJ. Anti-tumor necrosis factorantibody suppresses pulmonary antibacterial defenses [abstract]. Goldstein MM. Mastrangeli A. Antibody-mediated depletion of tumor necrosis factor. Djeu JY. Compartmentalization of the acute cytokine response in humans after intravenous endotoxin administration. et al. 230: 630 – 632 10 Nelson S. it is likely that the therapeutic benefits from these approaches will be fully realized. Beutler B. Passive immunization against tumor necrosis factor. Nat Med 1997. et al.treatment. Appleton. 1–33 2 Fels AO. J Infect Dis 1997. 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. Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon. The principles and practice of medicine. Dehoux MS. NY: Raven Press. Mason CM. Standiford T. Science 1986. Kolls J. Compartmentalized cytokine production within the human lung in unilateral pneumonia. As the complexities of the host-pathogen interaction are further dissected and unraveled. 2nd ed. et al. J Clin Invest 1991. 174:994 –1000 Greenberger MJ. Tumor necrosis factor. Am J Respir Crit Care Med 1997. Am J Respir Crit Care Med 1994. Infect Immun 1996. O’Reilly M. Chan J. J Appl Physiol 1993. Macrophages and polymorphonuclear neutrophils in lung defense and injury. Exp Lung Res 1991. Supinski E. J Infect Dis 1996. Nelson S. Manipulation of innate immunity may serve as an important adjuvant therapy in the treatment of both immunocompromised and immunocompetent patients with severe lung infections. In: Pennington JE. Liles WC. Tumor necrosis factor mediates lung antibacterial host defense in murine Klebsiella pneumonia. et al. Ostinelli J. 17:319 –332 Hebert JC. Granulocyte colonystimulating factor: role and relationships in infectious diseases. 172:1061–1075 Tazi A. 3:678 – 681 van der Poll T. et al. 113:981–986 7 Tracey KJ. et al. et al. et al. et al. Chastre J. Greenberger MJ. Compartmentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response.impairs pulmonary host defenses to Legionella pneumophila. J Appl Physiol 1986. et al. Expression of proinflammatory cytokines by flow-sorted alveolar macrophages in severe pneumonia. Martich GD. Granulocyte colony-stimulating factor and modulation of inflammatory cells in sepsis. 153:336 –342 Greenberger MJ. Am J Respir Cell Mol Biol 1991. Kunkel SL. Buhl R. References 1 Reynolds HY. Rosseau S.is required in the protective immune response against Mycobacterium tuberculosis in mice. Protective effects of tumor necrosis factor in experimental Legionella pneumophila infections of mice via activation of PMN function. Pathophysiology of pneumonia. 2:561–572 Jensen WA. Randow F. Clin Chest Med 1996. J Leukoc Biol 1988. 171:570 –575 12 Nelson S. 173:159 –165 Blanchard DK. J Cell Biol 1991. et al. 155:722–729 Brunda MJ. Lei D. Protective effect of Hospital-Acquired Infections: Realities of Risks and Resistance Downloaded from chestjournal. Interleukin-10 impairs host defense in murine pneumococcal pneumonia. et al. 43:429 – 435 Laichalk LL. Sporn M. et al. et al. Kasahara K.Conclusion Because of their role in mediating critical aspects of innate immunity. Neutralization of macrophage inflammatory protein-2 attenuates neutrophil recruitment and bacterial clearance in murine Klebsiella pneumonia. Reynolds HY. J Infect Dis 1995. 159:189 –194 11 Kolls JK. 4:140 –147 Nelson S. J Infect Dis 1989. 155:603– 608 Flynn JL. J Infect Dis 1995. 155:574 –577 Jaffe HA. 141:471–501 4 Nelson S. Summer WR. Kunkel SL. Streiter RM. 1892 Dale DC. Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung. 1988. Science 1985. 17:17–23 16 Boutten A. 72:3666 –3670 9 Old LJ. et al. The alveolar macrophage. et al. J Infect Dis 1987. Lowry SF. 143S:A393 13 Boujoukos AJ.org by guest on March 15. J Immunol 1996. 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. NY: D. Strieter RM. An endotoxin-induced serum factor that causes necrosis of tumors. Buurman WA. Interleukin-12. 150:710 –716 15 Kunkel SL. J Immunol 1995. 11:534 –541 Docke WD. Immunity 1995. Kassel RL. Strieter RM. Bagby GJ. Normal and defective respiratory host defenses. Eur Respir J 1998. Marchant A. 59:24 –28 6 Nathan C. IL-2 gene therapy protects mice in lethal Klebsiella pneumonia. et al. Syrbe U. J Infect Dis 1996. et al. et al. New York. Clin Chest Med 1995. Tumor necrosis factor (TNF). Kunkel SL. Keogh CV.to the human lung. Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. Seta N. ed. 74:3027–3033 14 Dehoux MS. et al. In vitro activation of the antibacterial activity of human pulmonary macrophages by recombinant interferon. Nioche S. Keogh CV. Schmidt RA. Rose RM. 2012 © 2001 American College of Chest Physicians . Bagby GJ. J Leukoc Biol 1994. Klein TW. Bagby GJ. Wasserman AS. Kunkel SL.impairs host defense during pneumococcal pneumonia in mice. et al. Am J Respir Crit Care Med 1996. 157:3006 –3012 Osler W. Bainton BG. J Leukoc Biol 1996. Respiratory infections: diagnosis and management. Expression and regulation of chemokines in bacterial pneumonia. Compartmentalized 424S 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. Kunkel SL. Summer W. Bagby G.
Nelson S. 2001 SUPPLEMENT 425S Downloaded from chestjournal. et al. 153S:A535 38 Daifuku R.chestpubs. Movahhed H. Shimozato T. Sharpe RW. Fotheringham N.recombinant human granulocyte colony-stimulating factor against pneumococcal infections in splenectomized mice. 90:587–592 39 McKenna PJ. 153S:A535. Time to resolution of morbidity: an endpoint for assessing the clinical cure of community-acquired pneumonia. Fotheringham N. 125:1075–1078 36 Smith WS. et al. Filgrastim (rhuG-CSF) enhances ciprofloxacin uptake and bactericidal activity of human neutrophils in vitro [abstract]. Therapeutic efficacy of granulocyte colony-stimulating factor alone and in combination with antibiotics against Pseudomonas aeruginosa infection in mice. Respir Med 1996. Am J Respir Crit Care Med 1996. et al. Arch Surg 1990. Ajiki Y. 58:2502–2509 CHEST / 119 / 2 / FEBRUARY. Andresen J.org by guest on March 15. 86:1301–1309 37 Nelson S. Blood 1995. Farkas S. et al. 40 Yasuda H. Am J Respir Crit Care Med 1996. 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. Filgrastim in the treatment of hospitalized patients with community acquired pneumonia (CAP) [abstract]. 2012 © 2001 American College of Chest Physicians . Infect Immun 1990. Sumnicht GE.
2012 © 2001 American College of Chest Physicians .419S This information is current as of March 15. 26 of which can be accessed free at: http://chestjournal.full.html References This article cites 36 articles.chestpubs.xhtml Reprints Information about ordering reprints can be found online: http://www. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format.chestpubs.2_suppl.org/site/misc/reprints.119.org/content/119/2_suppl/419S.org/content/119/2_suppl/419S.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article.Novel Nonantibiotic Therapies for Pneumonia* : Cytokines and Host Defense Steve Nelson Chest 2001.full.full.chestpubs. To sign up.chestpubs.org/content/119/2_suppl/419S.html#related-urls Permissions & Licensing Information about reproducing this article in parts (figures.org/site/misc/reprints.org by guest on March 15.chestpubs.html#ref-list-1 Cited Bys This article has been cited by 4 HighWire-hosted articles: http://chestjournal.1378/chest. See any online figure for directions. 419S-425S DOI 10.119. Downloaded from chestjournal. 2012 Updated Information & Services Updated Information and services can be found at: http://chestjournal. tables) or in its entirety can be found online at: http://www.chestpubs. select the "Services" link to the right of the online article.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue reading from where you left off, or restart the preview.