<b>Cytokine profiles in bronchoalveolar lavage fluid and blood in HIV‐seropositive patients with <i>Pneumocystis carinii</i> pneumonia</b>

Perenboom, R. M.; Sauerwein, Robert W.; Beckers, Pascal; Schijndel, A. C. H. W. Van; Steenwijk, Reindert P. van; Borleffs, Jan C. C.; Leusen, R. van; Meer, J.W.M. van der

doi:10.1046/j.1365-2362.1997.1170661.x

Cited by 22 publications

(17 citation statements)

References 40 publications

(47 reference statements)

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“…Antibody blockage of the IL-1 receptor in P. murina-infected splenocyte-reconstituted SCID mice leads to defective clearance of the organism (4). P. jirovecii induces IL-1 production by rodent splenocytes (42) and human macrophages (15), and IL-1 is additionally detected in the bronchoalveolar lavage fluid of human immunodeficiency virus-positive individuals with Pneumocystis pneumonia (31), suggesting that IL-1 production is part of the natural inflammatory response to P. murina. The roles of G-CSF and CXCL1/KC (GRO␣ in humans) in defense against P. murina have not been studied, although both of these molecules are present in bronchoalveolar lavage fluid from human immunodeficiency virus-positive individuals with Pneumocystis pneumonia (10,49).…”

Section: Discussionmentioning

confidence: 99%

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

Nelson

Metz

et al. 2009

Infect Immun

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Src family tyrosine kinases (SFKs) phosphorylate immunotyrosine activation motifs in the cytoplasmic tail of multiple immunoreceptors, leading to the initiation of cellular effector functions, such as phagocytosis, reactive oxygen species production, and cytokine production. SFKs also play important roles in regulating these responses through the activation of immunotyrosine inhibitory motif-containing inhibitory receptors. As myeloid cells preferentially express the SFKs Hck, Fgr, and Lyn, we questioned the role of these kinases in innate immune responses to Pneumocystis murina. Increased phosphorylation of Hck was readily detectable in alveolar macrophages after stimulation with P. murina. We further observed decreased phosphorylation of Lyn on its C-terminal inhibitory tyrosine in P. murina-stimulated alveolar macrophages, indicating that SFKs were activated in alveolar macrophages in response to P. murina. Mice deficient in Hck, Fgr, and Lyn exhibited augmented clearance 3 and 7 days after intratracheal administration of P. murina, which correlated with elevated levels of interleukin 1␤ (IL-1␤), IL-6, CXCL1/KC, CCL2/monocyte chemoattractant protein 1, and granulocyte colony-stimulating factor in lung homogenates and a dramatic increase in macrophage and neutrophil recruitment. Augmented P. murina clearance was also observed in Lyn ؊/؊ mice 3 days postchallenge, although the level was less than that observed in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice. A correlate to augmented clearance of P. murina in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice was a greater ability of alveolar macrophages from these mice to kill P. murina in vitro, suggesting that SFKs regulate the alveolar macrophage effector function against P. murina. Mice deficient in paired immunoglobulin receptor B (PIR-B), an inhibitory receptor activated by SFKs, did not exhibit enhanced inflammatory responsiveness to or clearance of P. murina. Our results suggest that SFKs regulate innate lung responses to P. murina in a PIR-B-independent manner.Although the advent of prophylactic therapy against Pneumocystis jirovecii alone or in combination with highly active antiretroviral therapy has reduced the incidence of pneumonia caused by this fungal pathogen, this infection remains the most prevalent opportunistic infection in individuals with AIDS (25). Furthermore, individuals receiving immunosuppressive therapies, such as individuals undergoing solid organ or hematopoietic cell transplantation, are a growing population susceptible to Pneumocystis pneumonia (34) (33). These observations warrant a more thorough examination of interactions between Pneumocystis and the host in order to define and develop new vaccine and immunotherapeutic approaches to treat Pneumocystis pneumonia.An intense area of research over the last decade is investigating how lung immune cells recognize and respond to inhaled pathogens, such as P. murina. After inhalation of P. murina into the lungs, one of the first interactions with the host is recognition by the alveolar macrophage. Our laboratory has prev...

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Section: Discussionmentioning

confidence: 99%

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

Nelson

Metz

et al. 2009

Infect Immun

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“…Mice with Pneumocystis pneumonia that developed HIR following adoptive transfer exhibited increased proinflammatory cytokines and chemokines and impaired respiratory function (23,40,41). In addition to IL-8, HIV and non-HIV patients with Pneumocystis pneumonia have increased levels of proinflammatory cytokines, eicosanoids, and other inflammatory mediators in their BALF; however, these patients also have increased levels of anti-inflammatory cytokines in their peripheral blood (4,5,20,21). The beneficial effects of CS in HIV ϩ patients with Pneumocystis pneumonia who are receiving anti-Pneumocystis drugs were thought to be due either to their anti-inflammatory properties or to their effects on the surfactant system (36).…”

Section: Discussionmentioning

confidence: 99%

Sensitized Splenocytes Result in Deleterious Cytokine Cascade and Hyperinflammatory Response in Rats withPneumocystisPneumonia despite the Presence of Corticosteroids

Thullen

Ashbaugh²,

Daly³

et al. 2004

Infect Immun

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The immune response to the opportunistic pulmonary pathogen Pneumocystis can have beneficial and harmful effects on the host despite the presence of corticosteroids. We hypothesized that this deleterious hyperinflammatory response is associated with exaggerated cytokine production. The adoptive transfer of at least 10 7 immune splenocytes reduced the cyst count in rats with corticosteroid-induced pneumocystosis. About 18% of these rats developed clinical illness, an increased lung weight/body weight (LW/BW) ratio, and elevated levels of interleukin 1␣ (IL-1␣), IL-1␤, IL-6, tumor necrosis factor alpha, IL-5, IL-10, and gamma interferon in the lungs. This hyperinflammatory reaction was not observed in rats that remained clinically well or in control rats. Thus, in this model, corticosteroids have little effect on the cytokine cascade or other adverse effects of the host immune response to Pneumocystis.

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“…However, exposure to IL-6 efficiently restores the conidiocidal activity of phagocytes, which suggests that fungal growth and fungal infectivity in the lung is sensitive to the action of the cytokine. Since a disregulated production of IL-6 is observed in patients with fungal infections [52][53][54], it is conceivable that targeting IL-6 or the IL-6-dependent path- …”

Section: Discussionmentioning

confidence: 99%

Impaired Antifungal Effector Activity but Not Inflammatory Cell Recruitment in Interleukin‐6–Deficient Mice with Invasive Pulmonary Aspergillosis

Cenci¹,

Mencacci²,

Casagrande³

et al. 2001

J INFECT DIS

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A murine model of infection, in which immunocompetent or immunosuppressed interleukin-6-deficient (IL-6(-/-)) mice were infected intranasally with Aspergillus fumigatus conidia and were monitored for parameters of fungal colonization and innate and adaptive immunity, was used to assess the role of IL-6 in invasive pulmonary aspergillosis (IPA). The results indicate that IL-6(-/-) mice were more susceptible than wild-type mice to IPA. Susceptibility was associated with increased inflammatory pathology, decreased antifungal effector functions of phagocytes, and impaired development of protective type 1 responses. Exposure to exogenous IL-6 restored antifungal effector activity.

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

Cited by 22 publications

References 40 publications

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

Sensitized Splenocytes Result in Deleterious Cytokine Cascade and Hyperinflammatory Response in Rats withPneumocystisPneumonia despite the Presence of Corticosteroids

Impaired Antifungal Effector Activity but Not Inflammatory Cell Recruitment in Interleukin‐6–Deficient Mice with Invasive Pulmonary Aspergillosis

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