Clinical review: A paradigm shift: the bidirectional effect of inflammation on bacterial growth. Clinical implications for patients with acute respiratory distress syndrome

Critical Care20016:24

DOI: 10.1186/cc1450

Published: 9 November 2001


Clinical studies have shown positive associations among sustained and intense inflammatory responses and the incidence of bacterial infections. We hypothesized that cytokines secreted by the host during acute respiratory distress syndrome may indeed favor the growth of bacteria and explain the association between exaggerated and protracted systemic inflammation and the frequent development of nosocomial infections. To test this hypothesis, we conducted in vitro studies evaluating the extracellular and intracellular growth response of three clinically relevant bacteria in response to graded concentrations of pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6. In these studies, we identified a U-shaped response of bacterial growth to pro-inflammatory cytokines. When the bacteria were exposed in vitro to a lower concentration of cytokines, extracellular and intracellular bacterial growth was not promoted and human monocytic cells were efficient in killing the ingested bacteria. Conversely, when bacteria were exposed to higher concentrations of pro-inflammatory cytokines, intracellular and extracellular bacterial growth was enhanced in a dose-dependent manner. The bidirectional effects of proinflammatory cytokines on bacterial growth may help to explain the frequent occurrence of nosocomial infections in patients with unresolving acute respiratory distress syndrome.

adult respiratory distress syndrome bacteria bacterial growth infection inflammation


The ability to generate and respond to signaling molecules establishes a mechanism for regulated cell-to-cell communication. Cells coordinate their growth and proliferation with autocrine and paracrine signaling by means of low molecular weight polypeptides called cytokines. Innate or natural immunity is a highly conserved defense mechanism against infections found in all multicellular organisms [1]. The inflammatory reaction is a fundamental component of the innate immune response, and its most proximal expression is characterized by the elaboration of proinflammatory cytokines – tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Response to cytokines is generally viewed as exclusive to cells containing a defined nucleus, since cytokines are intended to work on well-defined eukaryotic cells with consequent signal transduction events.

When proinflammatory cytokines are present in optimal concentration, they recruit both specific and nonspecific immune cells, nonlymphoid leukocytes (monocytes/ macrophages, neutrophils, basophils, and eosinophils), and lymphocytes to the site of assault and activate them, thereby helping to eradicate the assault and to restore homeostasis [2]. There are occasions, however, when the host defense response, in terms of inflammation, is exaggerated and protracted. In such cases, this primary defense process may instead cause enhanced tissue injury and mal-adaptive repair, leading to vital organ dysfunction and failure [3]. Reduction in the effective concentration of proinflamma-tory mediators is an important component in the resolution of inflammation [4].

The concepts of microbial etiology and pathogenesis of infectious diseases have undergone revisions since the pioneer researcher of microbial diseases, Robert Koch, postulated the criteria for microbial etiology of diseases. During the past decade, the emphasis in the study of the pathogenesis of infectious diseases has shifted from determining the function of the cellular players in the inflammatory response to the mediators that orchestrate this response [5]. The relationship between bacteria and inflammation is traditionally viewed as unidirectional. Bacteria trigger inflammation, which – as part of the host innate immune response – destroys bacteria and localizes the spread of infection. Although correct, this simple relationship does not provide a complete picture of the pathogen–host interaction in acute life-threatening infections. This unchallenged (preconditioned) view of the pathogen–host interaction has influenced for years the interpretation of objective clinical data in critical care medicine. In this paper, the clinical literature on nosocomial infections (NIs) in acute respiratory distress syndrome (ARDS) will be reviewed. The results will then be presented of a prospective study of ARDS patients that investigated longitudinally the relationship between circulatory and pulmonary proinflammatory cytokine levels, infections, and outcome. The findings of this study, as well as those of other groups, generated a novel hypothesis, suggesting that bacteria may grow in the presence of excessive cytokine levels. The results of recent in vitro studies from our group in support of this new hypothesis will also be reported.

Clinical observation in ARDS

ARDS is a frequent form of hypoxemic respiratory failure, characterized by the acute development of diffuse lung inflammation. In mortality data, after day three of ARDS, most patients die following a prolonged period of ventilatory support, during which they often develop fever and other criteria for systemic inflammatory response syndrome [6], clinical manifestations of infection [79], and multiple organ dysfunction syndrome [10,11]. In the medical literature, sepsis is associated with fatality in 36% to 90% of ARDS nonsurvivors [7,8,10,11]. At necropsy, 69% of ARDS non-survivors have histologic evidence of pneumonia [12]. These observations led to the hypothesis that, in ARDS, a direct correlation may exist between development of NIs, amplification of the systemic inflammatory response, and higher mortality [13]. Faist and coworkers [14] proposed a two-hit hypothesis in which NIs represent a second insult to a previously injured and primed host, converting a low-grade or regulated host response into an accelerated or dysregulated host response (accelerated systemic inflammatory response syndrome), triggering new or progressive organ dysfunction. Support for this hypothesis, however, relied only on clinical studies that did not use strict criteria for diagnosing NI. Furthermore, this broadly accepted pathophysiological hypothesis (second hit hypothesis) was never tested prospectively in ARDS.

Nosocomial infections and inflammation

Nosocomial infections and systemic inflammatory response in ARDS

We conducted a prospective study to investigate, at the onset of ARDS and during the progression of the disease, the longitudinal relationship between circulatory proinflamma-tory cytokine levels, infections, and outcome [15]. In most patients, the etiology of ARDS was pulmonary or extrapul-monary sepsis. We reported that, at the onset of ARDS, and over time, nonsurvivors (n = 17) had significantly (P < 0.001) higher plasma TNF-α, IL-1β, and IL-6 levels than survivors (n = 17) did [16]. During the first week of ARDS, plasma cytokine levels declined in all survivors, whereas they remained persistently elevated in all nonsurvivors. NIs were more frequent in patients with persistent cytokine elevation over time. The rate of nosocomial infection per day of mechanical ventilation was 1% in survivors and 8% in nonsur-vivors. Moreover, none of the proven (n = 36) or suspected (n = 55) NIs caused either a transient or a sustained increase in plasma TNF-α, IL-1β, IL-6, and IL-8 levels above preinfec-tion values [15]. This latter finding is in agreement with the recent understanding of downregulation (also called lipopolysaccharide [LPS] tolerance) of an activated system (see discussion in reference [15]). In these patients, a plasma IL-1β >400 pg/ml on day seven of ARDS was 100% accurate in predicting outcome [15]. Sixty-seven percent of NI developed after day 10 of ARDS, and among nonsurvivors, 15 out of 18 NIs developed while plasma IL-1β was >400 pg/ml. In addition to our work [15], one other study have described an association between high circulating IL-6 levels and increased rate of infections [17].

Ventilator-associated pneumonia and pulmonary inflammation in ARDS

The relationship between ventilator-associated pneumonia (VAP) and pulmonary inflammation was evaluated in a series of prospective studies. We evaluated with bilateral bron-choalveolar lavage (BAL) 94 ARDS patients with 172 episodes of suspected VAP and compared BAL results from contralateral sites [18]. Thirty-three of the 55 (60%) positive bronchoscopies had significant (>104 CFU/ml) growth in only one side. Episodes with bilateral significant growth were more likely to be polymicrobial, to have a bacterial growth >105 CFU/ml in the BAL, and to possess a higher percentage of polymorphonuclear (PMN) cells and intracellular microorganisms. These BAL findings indicated that episodes with a higher bacterial burden had cytological evidence of a more intense local inflammatory response and were more likely to be diffuse. Postmortem studies have also described a strong association between number of bacteria and severity of local inflammation [1921]. The traditional interpretation of these data would suggest that the more severe inflammation was the result of a higher bacterial burden; however, this relationship was challenged by the results of our prospective study [22].

In a longitudinal study of patients with ARDS, subjected to bilateral BAL weekly and when clinical manifestations of VAP developed, we reported that at the onset of ARDS and over time, nonsurvivors had significantly (P < 0.001) higher BAL TNF-α, IL-1β, and IL-6 levels than survivors did [22]. Nonsur-vivors had a higher rate of VAP than survivors [15]. In 21 episodes of VAP (16 unilateral and five bilateral pneumonia) there was excellent agreement between right and left BAL TNF-α, IL-1β, IL-6, total protein, and albumin levels. In other words, patients with unilateral pneumonia had similar TNF-α, IL-1β, and IL-6 levels in the BAL obtained from the lung with significant bacterial growth compared to the BAL from the contralateral lung without growth [15]. Furthermore, VAPs were not associated with either a transient or a sustained increase in BAL TNF-α, IL-1β, IL-6, and IL-8 levels above pre-infection values [15]. In agreement with our results, the findings of a recent experimental study of gram-negative pneumonia indicated that persistent elevation in BAL proin-flammatory cytokines is associated with failure to clear intra-pulmonary bacteria, despite a large influx of PMN in the airspaces [23].

Experimental and human studies have shown that a lung affected by ARDS is impaired in its ability to clear a bacterial challenge. Several intrinsic defects have been previously implicated, primarily those related to changes in the alveolar environment and the function of phagocytic cells [2]. Poly-morphonuclear cells recruited into the airspaces of patients with ARDS have shown evidence of impaired microbicidal activity [24,25]; this mechanism partly explains the lung's inability to clear bacteria in spite of intense local inflammation. Furthermore, PMN clearing of bacteria is dose dependent, and the efficiency of PMN bactericidal activity decreases with increasing bacterial load [26].

Recent understanding of bacteria and cytokine interaction

In the interaction between a microorganism and its host, the host's defense does not go unchallenged [27]. Several reports have shown that DNA viruses have the ability to interfere with extracellular cytokines or inhibit cytokine synthesis [27]. Until recently, very little was known about the ability of bacteria to interfere with, or to utilize, extracellular cytokines secreted by the host cells or intracellular cytokines within phagocytic cells. Recent reports have shown that certain bacteria have receptors for cytokines IL-1β and TNF-α, and that exposure of bacteria to these cytokines enhanced their growth [2830].


The surfaces of bacteria have receptors for proinflammatory cytokines. Gram-negative bacteria have receptors for TNF-α and IL-1β [2931], and the virulence property of the bacterium is altered as a consequence of cytokine binding [30]. Porat et al. [28] reported that virulent strains of Escherichia coli express receptors for IL-1β and demonstrated enhanced extracellular in vitro growth in the presence of biologically active recombinant IL-1β. Luo et al. [30] reported that TNF-α could bind efficiently to many strains of gram-negative bacteria and that TNF-α-bacterium complexes can interact with TNF-α receptors present on eukaryotic cells. They also showed that TNF-α binding enhanced bacterial invasion of HeLa cells and phagocytosis by human and murine macrophages [30]. We recently reported that the surfaces of Staphylococcus aureus have receptors for IL-1β [32].

Enhanced bacterial growth with cytokines

Enhanced bacterial growth in the presence of cytokines has been reported for E. coli (IL-1β [28], interferon-γ [33], IL-2 [34], and granulocyte macrophage colony stimulating factor [34]) and S. aureus (IL-4) [35]. Two studies have reported that the intracellular growth of Mycobacterium avium–intracellular complex was enhanced in human peripheral blood monocytes activated with the cytokines IL-3, IL-6, and granulocyte macrophage colony stimulating factor [36,37].

Anti-inflammatory cytokines have also been reported to promote bacterial growth. Two studies have shown that IL-10 and IL-4 can enhance the intracellular replication of bacteria. Park and Skerrett [38] reported that priming of human monocytes with IL-10 significantly enhanced the intracellular growth of Legionella pneumophila. Hultgren et al. [35] reported reduced growth of S. aureus in the joints of an IL-4-deficient mouse and showed that exposure of macrophages to IL-4 reduced intracellular killing of S. aureus without impairing phagocytosis. We recently reported that the extra-cellular growth of S. aureus is enhanced in the presence of IL-1 receptor antagonist [32].

New hypothesis and hypothesis testing

The findings from our studies described above [15,16,22] suggested that final outcome in patients with ARDS is related to the magnitude and duration of the host inflammatory response, and that intercurrent NIs might be an epiphenomenon of prolonged intense inflammation. The increased rate of NIs might be explained by impaired host defense response. We hypothesized, however, that cytokines secreted by the host during ARDS may indeed favor the growth of bacteria and explain the association between an exaggerated and protracted release of cytokines and the frequent development of NIs.

To test this hypothesis, we conducted in vitro studies evaluating the extracellular and intracellular growth response of three clinically relevant bacteria in response to graded concentrations of proinflammatory cytokines TNF-α, IL-1β, and IL-6 [32,3941]. The bacteria used were fresh isolates of S. aureus, Pseudomonas aeruginosa, and Acinetobacter sps obtained from patients with ARDS. The bacteria were grown in 3 ml of RPMI/DMEM medium without serum or antibiotics. Intracellular growth was tested in the human monocytic cell line, U937, and in blood monocytes of normal healthy volunteers.

In these studies, we identified a U-shaped response of bacterial growth to proinflammatory cytokines. When the bacteria were exposed in vitro to a lower concentration (10–250 pg) of TNF-α, IL-1β, or IL-6 – similar to the plasma values detected in ARDS survivors [16] – extracellular and intracel-lular bacterial growth was not promoted, and human monocytic cells were efficient in killing the ingested bacteria [39,40]. Conversely, when bacteria were exposed to higher concentrations of these of proinflammatory cytokines – similar to the plasma values detected in ARDS nonsurvivors [16] – intracellular and extracellular bacterial growth were enhanced in a dose-dependent manner [39,40]. Blockade by specific neutralizing monoclonal antibodies significantly inhibited cytokine-induced extracellular and intracelullar bacterial growth [39,40].

The effects of cytokines on extracellular bacterial growth were seen only with fresh isolates and were lost after six in vitro passages [39]. These findings indicate that, in the host milieu, S. aureus, Ps. aeruginosa, and Acinetobacter sps may acquire a phenotypic ability to use cytokines as growth factors; subsequent removal of these pathogens from such milieu (after six in vitro passages) resulted in the loss of the acquired phenotype. This phenomenon of loss of responsiveness to cytokines was also recorded by Porat and collaborators [31].

Effects of LPS on intracellular bacterial growth

The intracellular growth of S. aureus, Ps. aeruginosa, and Acinetobacter sps was also tested after exposure of U937 monocytic cells to graded concentrations of LPS. At low priming concentrations of LPS, we observed a significant reduction in intracellular bacterial growth compared to the control. At a priming concentration of LPS equal to, or greater than, 100 ng, however, all three bacterial isolates had a significant growth enhancement compared to the control (P < 0.0001, for all three bacteria). Taken together, our findings indicate that there may be a threshold of cellular activation at which phagocytic cells effectively kill ingested bacteria. Above this threshold of cellular activation, however, the intracellular micromilieu becomes favorable to the survival and replication of the ingested bacteria. It is likely that bacteria that are internalized, and under selective pressure, may adapt to an otherwise hostile microenvironment by switching on novel gene expression that enables them to utilize cytokines as their growth factors.

Effects of methylprednisolone on intracellular bacterial growth

We exposed U937 monocytic cells primed with the highest concentration of LPS (10 μg) to escalating concentrations (0 μg, 25 μg, 50 μg, 75 μg, 100 μg, 150 μg, and 250 μg) of methylprednisolone and quantified both intracellular bacterial growth and the intracellular transcription of TNF-α, IL-1β, and IL-6. We found that exposure of LPS-primed U937 monocytic cells to methylprednisolone prior to infection affected (in a dose-dependent manner) the mRNA expression of TNF-α, IL-1β, and IL-6, and the in vitro intracellular bacterial growth of internalized S. aureus, Ps. aeruginosa, and Acinetobacter sps [41].

The impairment in intracellular bacterial killing correlated with the increased expression of proinflammatory cytokines, while restoration of monocyte killing function upon exposure to methylprednisolone coincided with the downregulation of the expression of TNF-α, IL-1β, and IL-6. We found that, at the two highest concentrations of methylprednisolone (150 μg and 250 μg), the mRNA expression of all three cytokines was significantly blunted, irrespective of the LPS concentration. Hence, we presume that bacterial survival and replication within the phagocytic cells are functions of the cytokines expressed by such cells. In the presence of excessive activation, the intracellular environment appears to favor the emergence of new phenotypes of bacteria that are capable of utilizing cytokines for their growth. By showing that methyl-prednisolone can reduce (in a dose-dependent manner) the mRNA expression of TNF-α, IL-1β, and IL-6, and the intracel-lular bacterial growth of the bacteria, we provide experimental evidence to suggest a cause-and-effect relationship between excessive inflammation and bacterial growth.

Bacteria and cytokine interactions

It is unclear how bacteria may use cytokines for their growth, since bacteria are prokaryotes without a defined nucleus and cytokines are intended to work on well-defined eukaryotic cells with consequent signal transduction events. In a host milieu, however, bacteria may adapt to eukaryotic cellular processes [42]. Although, the subsequent sequence of intra-cellular events has not been delineated, it is possible that bacteria might use cytokines through receptor-mediated, signal-transduction-induced activities that would require the presence of biochemical processes akin to those seen in eukaryotic cells. Cytokines may act on bacteria through a signaling process similar to that of eukaryotes, but involving different biochemical pathways, or bacteria may break down cytokines into biologically active fragments that are transported across the bacterial cell membranes and act on specific gene transcription and translation.

To further elucidate the complex interactions between bacteria and cytokines, we conducted in vitro experiments using S. aureus to demonstrate the presence of IL-1 receptors on the surface of S. aureus, and to localize the region(s) of IL-1β that enhance the extracellular growth of S. aureus. We identified an IL-1β receptor on the surface of the bacterium and we utilized five linear peptide fragments of human IL-1β and whole biologically active molecules of both IL-1 receptor antagonist and IL-1β to study their effects on extracellular growth of S. aureus. Of the five peptide fragments studied, the 208–240 peptide fragment demonstrated the most pronounced effect on the growth of S. aureus. Previously, this fragment has been shown to be pyrogenic and to enhance sleep in rabbits [43]. This peptide fragment, however, does not have mitogenic activity on T cells in vitro, indicating its probable lack of ability to interact specifically with IL-1 receptor (although the possibility of a receptor–ligand interaction cannot be completely ruled out). This peptide (208–240) enhanced the growth of S. aureus approximately 22-fold compared to the control (bovine serum albumin). Another peptide spanning amino acids 118–147 also enhanced the extracellular growth of S. aureus significantly, although much less efficiently, than the peptide fragment 208–240. No significant effects were exerted on S. aureus growth by the other 3 fragments studied. No biological activities in any other systems have been reported for any of the peptides studied other than for the one spanning 208–240.

Several proteinases are released from S. aureus into the extracellular medium [44] and it is therefore possible that such enzymes may cleave the IL-1β molecule into peptide fragments. Such short peptide fragments may then be transported across the bacterial cell membrane and act as direct growth factors, or as transcription factors, for the production of bacterial growth factors. This remains speculative at this time since there is no direct proof of such cleavage activities of S. aureus extracellular proteinases on IL-1β. There are, however, reports of proteolytic cleavages of IL-2, TNF-α, and/or interferon-γ by bacterial products of Ps. aeruginosa and Legionella pneumophila [5].


The bidirectional effects of proinflammatory cytokines on bacterial growth may help explain the frequent occurrence of NIs in patients with unresolving ARDS. Table 1 shows the traditional versus alternative interpretations of clinical findings in ARDS. If NIs in unresolving ARDS are indeed an epiphenomenon of exaggerated inflammation, it follows that treatment modalities that effectively decrease cytokine synthesis may reduce the incidence or severity of NIs.
Table 1

Traditional versus alternative interpretation of clinical data on nosocomial infections and inflammation in ARDS


Traditional interpretation

Alternative interpretation

Inflammation and bacteria

Inflammation kills bacteria

Regulated inflammation kills bacteria while excessive (unregulated) inflammation may enhance bacterial growth

Nosocomial infections

More frequent in nonsurvivors

More frequent in patients with persistent cytokine elevation


Amplify inflammation (second hit hypothesis) and worsen multiple organ dysfunction syndrome

Do not amplify inflammation (downregulation, or LPS tolerance)

Systemic inflammation in ARDS

Progression is amplified by nosocomial infections (≥ day 3 of ARDS)

Progression is determined prior to day 3, by the success and/or failure of the host regulatory mechanisms

Glucocorticoid treatment in patients with unregulated systemic inflammation

Causes immunosuppression and enhances the risk for developing infections

If given in low doses for a prolonged period (≥ 7 days) may have an important immunomodulatory effect in regulating excessive inflammation and restoring homeostasis

ARDS, acute respiratory distress syndrome; LPS, lipopolysaccharide.



acute respiratory distress syndrome

BAL : 

bilateral bronchoalveolar lavage

CFU : 

colony-forming unit

IL : 


LPS : 


NI : 

nosocomial infection

PMN : 


TNF : 

tumor necrosis factor

VAP : 

ventilator-associated pneumonia.


Authors’ Affiliations

Divisions of Pulmonary and Critical Care Medicine and Infectious Disease, Department of Medicine, University of Tennessee


  1. Suffredini AF, Fantuzzi G, Badolato R, Oppenheim JJ, O'Grady NP: New insights into the biology of the acute phase response. J Clin Immunol 1999, 19:203–214.PubMedView Article
  2. Meduri GU, Estes RJ: The pathogenesis of ventilator-associated pneumonia: II. The lower respiratory tract. Intensive Care Med 1995, 21:452–461.PubMedView Article
  3. Meduri GU: The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment. Eur Respir J 1996, 9:2650–2670.PubMedView Article
  4. Rossi AG, Haslett C: Inflammation, cell injury, and apoptosis. In Proinflammatory and Anti-inflammatory Peptides. Edited by Said SI. New York: Marcel Dekker Inc; 1998, 9–24.
  5. Wilson M, Seymour R, Henderson B: Bacterial perturbation of cytokine networks. Infect Immun 1998, 66:2401–2409.PubMed
  6. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992, 101:1644–1655.PubMedView Article
  7. Montgomery AB, Stager MA, Carrico CJ, Hudson LD: Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985, 132:485–489.PubMed
  8. Andrews CP, Coalson JJ, Smith JD, Johanson WG Jr: Diagnosis of nosocomial bacterial pneumonia in acute, diffuse lung injury. Chest 1981, 80:254–258.PubMedView Article
  9. Seidenfeld JJ, Pohl DF, Bell RC, Harris GD, Johanson WG Jr: Incidence, site, and outcome of infections in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1986, 134:12–16.PubMed
  10. Bell RC, Coalson JJ, Smith JD, Johanson WG Jr: Multiple organ system failure and infection in adult respiratory distress syndrome. Ann Intern Med 1983, 99:293–298.PubMed
  11. Suchyta MR, Clemmer TP, Elliott CG, Orme JF Jr, Weaver LK: The adult respiratory distress syndrome. A report of survival and modifying factors. Chest 1992, 101:1074–1079.PubMedView Article
  12. Meduri GU: Late adult respiratory distress syndrome. New Horiz 1993, 1:563–577.PubMed
  13. Bone RC: Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med 1996, 24:163–172.PubMedView Article
  14. Faist E, Baue AE, Dittmer H, Heberer G: Multiple organ failure in polytrauma patients. J Trauma 1983, 23:775–787.PubMedView Article
  15. Headley AS, Tolley E, Meduri GU: Infections and the inflammatory response in acute respiratory distress syndrome. Chest 1997, 111:1306–1321.PubMedView Article
  16. Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K: Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995, 107:1062–1073.PubMedView Article
  17. Romani L, Mencacci A, Cenci E, Spaccapelo R, Toniatti C, Puc-cetti P, Bistoni F, Poli V: Imparied neutrophil response and CD4 + T helper cell development in interleukin 6-deficient mice infect with Candida albicans . J Exp Med 1996, 183:1345–1355.PubMedView Article
  18. Meduri GU, Reddy RC, Stanley T, El-Zeky F: Pneumonia in acute respiratory distress syndrome. A prospective evaluation of bilateral bronchoscopic sampling. Am J Respir Crit Care Med 1998, 158:870–875.PubMed
  19. Rouby JJ, Martin De Lassale E, Poete P, Nicolas MH, Bodin L, Jarlier V, Le Charpentier Y, Grosset J, Viars P: Nosocomial bron-chopneumonia in the critically ill. Histologic and bacteriologic aspects. Am Rev Respir Dis 1992, 146:1059–1066.PubMed
  20. Johanson WG Jr, Seidenfeld JJ, Gomez P, de los Santos R, Coalson JJ: Bacteriologic diagnosis of nosocomial pneumonia following prolonged mechanical ventilation. Am Rev Respir Dis 1988, 137:259–264.PubMed
  21. Chastre J, Fagon JY, Bornet-Lecso M, Calvat S, Dombret MC, al Khani R, Basset F, Gibert C: Evaluation of bronchoscopic techniques for the diagnosis of nosocomial pneumonia. Am J Respir Crit Care Med 1995, 152:231–240.PubMed
  22. Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A: Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 1995, 108:1303–1314.PubMedView Article
  23. Fox-Dewhurst R, Alberts MK, Kajikawa O, Caldwell E, Johnson MC, Skerrett SJ, Goodman RB, Ruzinski JT, Wong VA, Chi EY, Martin TR: Pulmonary and systemic inflammatory responses in rabbits with gram-negative pneumonia. Am J Respir Crit Care Med 1997, 155:2030–2040.PubMed
  24. Martin TR, Pistorese BP, Hudson LD, Maunder RJ: The function of lung and blood neutrophils in patients with the adult respiratory distress syndrome. Implications for the pathogenesis of lung infections. Am Rev Respir Dis 1991, 144:254–262.PubMed
  25. Chollet-Martin S, Jourdain B, Gibert C, Elbim C, Chastre J, Gougerot-Pocidalo MA: Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. Am J Respir Crit Care Med 1996, 154:594–601.PubMed
  26. Clawson CC, Repine JE: Quantitation of maximal bactericidal capability in human neutrophils. J Lab Clin Med 1976, 88:316–327.PubMed
  27. Kotwal GJ: Microorganisms and their interaction with the immune system. J Leukocyte Biol 1997, 62:415–429.PubMed
  28. Porat R, Clark BD, Wolff SM, Dinarello CA: Enhancement of growth of virulent strains of Escherichia coli by interleukin-1. Science 1991, 254:430–432.PubMedView Article
  29. Zav'yalov VP, Chernovskaya TV, Navolotskaya EV, Karlyshev AV, MacIntyre S, Vasiliev AM, Abramov VM: Specific high affinity binding of human interleukin 1 beta by Caf1A usher protein of Yersinia pestis. FEBS Lett 1995, 371:65–68.PubMedView Article
  30. Luo G, Niesel DW, Shaban RA, Grimm EA, Klimpel GR: Tumor necrosis factor alpha binding to bacteria: evidence for a high-affinity receptor and alteration of bacterial virulence properties. Infect Immun 1993, 61:830–835.PubMed
  31. Porat RB, Clark D, Wolf SM, Dinarello CA: IL-1b and Escherichia coli. Science 1992, 258:1562–1563.View Article
  32. Kanangat S, Bronze MS, Meduri GU, Postlethwaite A, Stentz F, Tolley E, Schaberg D: Enhanced extracellular growth of Staphylococcus aureus in the presence of selected linear peptide fragments of human interleukin (IL)-1beta and IL-1 receptor antagonist. J Infect Dis 2001, 183:65–69.PubMedView Article
  33. Hogan JS, Todhunter DA, Smith KL, Schoenberger PS, Sor-dillo LM: Growth responses of coliform bacteria to recombinant bovine cytokines. J Dairy Sci 1993, 76:978–982.PubMedView Article
  34. Denis M, Campbell D, Gregg EO: Interleukin-2 and granulocyte-macrophage colony-stimulating factor stimulate growth of a virulent strain of Escherichia coli . Infect Immun 1991, 59:1853–1856.PubMed
  35. Hultgren O, Kopf M, Tarkowski A: Staphylococcus aureus-induced septic arthritis and septic death is decreased in IL-4-deficient mice: role of IL-4 as promoter for bacterial growth. J Immunol 1998, 160:5082–5087.PubMed
  36. Denis M, Gregg EO: Recombinant tumour necrosis factor-alpha decreases whereas recombinant interleukin-6 increases growth of a virulent strain of Mycobacterium avium in human macrophages. Immunology 1990, 71:139–141.PubMed
  37. Shiratsuchi H, Johnson JL, Ellner JJ: Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes. J Immunol 1991, 146:3165–3170.PubMed
  38. Park DR, Skerrett SJ: IL-10 enhances the growth of Legionella pneumophila in human mononuclear phagocytes and reverses the protective effect of IFN-γ: differential responses of blood monocytes and alveolar macrophages. J Immunol 1996, 157:2528–2538.PubMed
  39. Meduri GU, Kanangat S, Stefan J, Tolley E, Schaberg S: Cytokines IL-1beta, IL-6, and TNF-alpha enhance in vitro growth of bacteria. Am J Respir Crit Care Med 1999, 160:961–967.PubMed
  40. Kanangat S, Meduri GU, Tolley EA, Patterson DR, Meduri CU, Pak C, Griffin JP, Bronze MS, Schaberg DR: Effects of cytokines and endotoxin on the intracellular growth of bacteria. Infect Immun 1999, 67:2834–2840.PubMed
  41. Meduri GU, Kanangat S, Bronze MS, Patterson D, Meduri CU, Pak C, Tolley E, Schaberg D: Effects of methylprednisolone on intracellular bacterial growth. Clin Diagn Lab Immunol 2001, in press.
  42. Falkow S: Perspectives series: host/pathogen interactions. Invasion and intracellular sorting of bacteria: searching for bacterial genes expressed during host/pathogen interactions. J Clin Invest 1997, 100:239–243.PubMedView Article
  43. Obal F Jr, Opp M, Cady AB, Johannsen L, Postlethwaite AE, Poppleton HM, Seyer JM, Krueger JM: Interleukin 1 alpha and an interleukin 1 beta fragment are somnogenic. Am J Physiol 1990, 259:R439-R446.PubMed
  44. Arvidson SO: Extracellular enzymes from S. aureus. In Staphylococci and Staphylococcal Infections. Edited by Easmon CSF, Adlam C. London: Academic Press; 1983, 745–799.


© BioMed Central Ltd 2002