A Controlled Trial of Early Adjunctive Treatment with Corticosteroids for<i>Pneumocystis carinii</i>Pneumonia in the Acquired Immunodeficiency Syndrome

Bozzette, Samuel A.; Sattler, Fred R.; Chiu, John T.; Wu, Anqi; Gluckstein, Daniel; Kemper, Carol A.; Bartok, Agnes; Niosi, J; Abramson, Ian; Coffman, Jenny

doi:10.1056/nejm199011223232104

Cited by 446 publications

(177 citation statements)

References 34 publications

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“…It is therefore possible that without this confounding factor, concentrations of proinflammatory cytokines in BAL fluid in PCP patients would be even higher. Moreover, our principle conclusion of divergence of local and systemic cytokine profile is supported by similar data in HIV-patients with PCP and a rat model [20,26].…”

Section: Cytokines In Hiv+ Patients With Pcp 337supporting

confidence: 77%

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**Cytokine profiles in bronchoalveolar lavage fluid and blood in HIV‐seropositive patients with Pneumocystis carinii pneumonia**

Perenboom

Sauerwein²,

Beckers³

et al. 1997

Eur J Clin Investigation

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Abstract. Concentrations and ex vivo production of interleukin 1b (IL-1), tumour necrosis a (TNF), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA) and TNF soluble receptors (sTNF-receptors, P55 and P75) were measured in bronchoalveolar lavage (BAL) fluid and blood in 23 HIV-seropositive (HIV+) patients with Pneumocystis carinii pneumonia (PCP) and compared with values found in healthy HIV-seronegative (HIV-) controls and asymptomatic HIV+ subjects. Concentrations of the proinflammatory cytokine IL-1b were increased in BAL fluid of HIV+ patients with PCP (184 Ϯ 47 pg mL -1 ) compared with undetectable levels in healthy control subjects (P = 0 . 0001). In plasma of these patients higher concentrations of the anti-inflammatory cytokine IL-1RA were found during acute PCP than after recovery (2 . 1 Ϯ 0 . 7 vs. 0 . 5 Ϯ 0 . 2 ng mL -1 , P = 0 . 01). No correlations could be found between cytokine concentrations and clinical severity of the infection. Corticosteroid treatment did not influence cytokine concentrations in BAL or blood, nor did it suppress the production in alveolar cells. In whole-blood cultures, however, lipopolysaccharide (LPS)-stimulated production was significantly suppressed for IL-1 (1 . 3 vs. 5 . 5 ng mL -1 , P = 0 . 009) and for IL-6 (0 . 6 vs. 2 . 5 ng mL -1 , P = 0 . 01). The overall data show that in HIV+ patients with PCP (similar to what we had found previously in HIVpatients with PCP) proinflammatory cytokines are more prominently present in BAL, whereas anti-inflammatory reaction is predominant in the circulation.

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Section: Cytokines In Hiv+ Patients With Pcp 337supporting

confidence: 77%

“…In the four participating centres patients were given adjunctive corticosteroids when the PO 2 was equal to or less than 8 kPa, a lower threshold than mentioned in the NIH consensus [20].…”

Section: Patientsmentioning

confidence: 99%

**Cytokine profiles in bronchoalveolar lavage fluid and blood in HIV‐seropositive patients with Pneumocystis carinii pneumonia**

Perenboom

Sauerwein²,

Beckers³

et al. 1997

Eur J Clin Investigation

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“…Additional investigations indicate that P. carinii cell wall ␤-glucans strongly stimulate neutrophilic lung inflammation (3,11). Nonspecific anti-inflammatory therapies, such as adjunctive corticosteroids, have significantly decreased mortality during severe PC pneumonia (31). Thus, a better understanding of glucan-induced inflammation may provide novel means by which lung inflammation can be selectively modulated during this infection.…”

Section: Discussionmentioning

confidence: 99%

Pneumocystis carinii Cell Wall β-Glucan Induces Release of Macrophage Inflammatory Protein-2 from Alveolar Epithelial Cells via a Lactosylceramide-mediated Mechanism

Hahn¹,

Evans²,

Kottom³

et al. 2003

Journal of Biological Chemistry

138

150

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Infiltration of the lungs with neutrophils promotes respiratory failure during severe Pneumocystis carinii (PC) pneumonia. Recent studies have shown that alveolar epithelial cells (AECs), in addition to promoting PC attachment, also participate in lung inflammation by the release of cytokines and chemokines. Herein, we demonstrate that a PC ␤-glucan rich cell wall isolate (PCBG) stimulates the release of macrophage inflammatory protein-2 (MIP-2) from isolated AECs through a lactosylceramidedependent mechanism. The results demonstrate that MIP-2 mRNA and protein production is significantly increased at both early and late time points after PCBG challenge. Although CD11b/CD18 (Mac-1, CR3) is the most widely studied ␤-glucan receptor, we demonstrate that CD11b/CD18 is not present on AECs. This study instead demonstrates that preincubation of AECs with an antibody directed against the membrane glycosphingolipid lactosylceramide (CDw17) results in a significant decrease in MIP-2 secretion. Preincubation of the antiCDw17 antibody with solubilized lactosylceramide reverses this effect. Furthermore,

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“…These exuberant host inflammatory responses, although necessary for clearance of infection, further promote lung injury resulting in respiratory failure and excessive morbidity. Therapeutic maneuvers that limit excessive inflammation are beneficial to patients with Pneumocystis pneumonia (45)(46)(47)(48). These observations provide considerable initiative to fully understand the mechanisms and signaling pathways induced by P. carinii cell wall glucans, which trigger inflammatory activation of macrophages (8).…”

Section: Discussionmentioning

confidence: 99%

Pneumocystis carinii Cell Wall β-Glucans Initiate Macrophage Inflammatory Responses through NF-κB Activation

Lebron¹,

Vassallo²,

Puri³

et al. 2003

Journal of Biological Chemistry

109

101

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␤-Glucans are major structural components of fungi. We have recently reported that the pathogenic fungus Pneumocystis carinii assembles a ␤-glucan-rich cell wall that potently activates alveolar macrophages to release pro-inflammatory cytokines and chemokines. Purified P. carinii ␤-glucans predictably induce both cytokine generation and associated neutrophilic lung inflammation. Herein, we demonstrate that P. carinii ␤-glucaninduced macrophage stimulation results from activation of NF-B. Although analogous to macrophage activation induced by bacterial lipopolysaccharide (LPS), P. carinii ␤-glucan-induced macrophage NF-B activation exhibits distinctly different kinetics, with slower induction and longer duration compared with LPS stimulation. Macrophage activation in response to P. carinii ␤-glucan was also substantially inhibited with the NF-B antagonist pyrrolidine dithiocarbamate. In addition to different kinetics of NF-B activation, P. carinii ␤-glucan and LPS also utilize different receptor systems to induce macrophage activation. Macrophages from Toll-like receptor 4-deficient and wild type mice produced equivalent amounts of tumor necrosis factor ␣ when stimulated with P. carinii ␤-glucan. However, Toll-like receptor 4-deficient macrophages were refractory to stimulation with LPS. In contrast, MyD88-deficient macrophages exhibited a significant (though partial) blunted response to P. carinii ␤-glucan. These data demonstrate that P. carinii ␤-glucan acts as potent inducer of macrophage activation through NF-B utilizing cellular receptors and signaling pathways distinct from LPS.

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A Controlled Trial of Early Adjunctive Treatment with Corticosteroids forPneumocystis cariniiPneumonia in the Acquired Immunodeficiency Syndrome

Cited by 446 publications

References 34 publications

**Cytokine profiles in bronchoalveolar lavage fluid and blood in HIV‐seropositive patients with Pneumocystis carinii pneumonia**

**Cytokine profiles in bronchoalveolar lavage fluid and blood in HIV‐seropositive patients with Pneumocystis carinii pneumonia**

Pneumocystis carinii Cell Wall β-Glucan Induces Release of Macrophage Inflammatory Protein-2 from Alveolar Epithelial Cells via a Lactosylceramide-mediated Mechanism

Pneumocystis carinii Cell Wall β-Glucans Initiate Macrophage Inflammatory Responses through NF-κB Activation

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