Tumor necrosis factor alpha-mediated host defense against Pneumocystis carinii.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
A H Limper
Publications and source records attributed to A H Limper.
Candida albicans induces the release of inflammatory mediators from human peripheral blood monocytes.
Candida albicans (C. albicans) is a major nosocomial pathogen. We examined arachidonic acid (AA) and cytokine production by monocytes stimulated with C. albicans. [14C]-AA labeled monocytes released 8.9 +/- 2.3% of the incorporated AA following stimulation with live C. albicans (C. albicans: monocyte of 16:1) (P = 0.0002). Prior studies indicate that soluble alpha-mannans and beta-glucans antagonize mannose and beta-glucan receptors, respectively. Preincubation of monocytes with alpha-mannan (100 micrograms/ml) caused 45.8 +/- 5.7% inhibition of [14C]-AA release, whereas beta-glucan (100 micrograms/ml) yielded 43.7 +/- 6.0% inhibition (P < 0.05 for each compared to control). Additionally, monocytes stimulated with C. albicans also released interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8). However, alpha-mannan or beta-glucan failed to inhibit IL-1 beta release. These data indicate that C. albicans induces monocytes to release AA and inflammatory cytokines. Furthermore, AA, but not cytokine liberation, is partially mediated by alpha-mannan and beta-glucan components of the fungus.
Arachidonic Acid↗
Drug-induced interstitial lung disease.
Drugs can have multiple different adverse effects on the lungs, airways, pleura, mediastinum, and the interstitium. Their appearance can mimic other interstitial lung diseases and, for the most part, drug-induced interstitial lung disease is a condition of exclusion rather than a specific entity that can be diagnosed with imaging studies or histology. It is important to be aware of all the potential adverse effects of drugs on the lung in order to recognize the condition and to discontinue the drug as soon as possible, as death will result in many of the situations discussed here if appropriate measures are not taken.
Anti-Arrhythmia Agents↗
Fungal beta-glucan interacts with vitronectin and stimulates tumor necrosis factor alpha release from macrophages.
beta-Glucans are polymers of D-glucose which represent major structural components of fungal cell walls. It was shown previously that fungi interact with macrophages through beta-glucan receptors, thereby inducing release of tumor necrosis factor alpha (TNF-alpha). Additional studies demonstrated that vitronectin, a host adhesive glycoprotein, binds to fungi and enhances macrophage recognition of these organisms. Since vitronectin contains a carbohydrate-binding region, we postulated that vitronectin binds fungal beta-glucans and subsequently augments macrophage TNF-alpha release in response to this fungal component. To study this, we first determined the release of TNF-alpha from alveolar macrophages stimulated with fungal beta-glucan. Maximal TNF-alpha release occurred with moderate concentrations of beta-glucan (100 to 200 micrograms/ml), whereas higher concentrations of beta-glucan (> or = 500 micrograms/ml) caused apparent suppression of the TNF-alpha activity released. This suppression of TNF-alpha activity by high concentrations of beta-glucan was mediated by the particulate beta-glucan binding soluble TNF-alpha, through the lectin-binding domain of the cytokine, rendering the TNF-alpha less available for measurement. Next, we assessed the interaction of vitronectin with beta-glucan. Binding of 125I-vitronectin to particulate fungal beta-glucan was dose dependent and specifically inhibitable by unlabeled vitronectin. Furthermore, treatment of beta-glucan with vitronectin substantially augmented macrophage TNF-alpha release in response to this fungal component. These findings demonstrate that fungal beta-glucan can directly modulate TNF-alpha release from macrophages. Further, these studies indicate that the host adhesive glycoprotein vitronectin specifically binds beta-glucan and augments macrophage cytokine release in response to this fungal element.
Animals↗
Tissue localization of transforming growth factor-beta1 in pulmonary eosinophilic granuloma.
Pulmonary eosinophilic granuloma is characterized by infiltration of the lungs with fibronodular lesions containing specialized Langerhans' cells. In some patients, progressive pulmonary fibrosis leads to significant respiratory impairment. Transforming growth factor-beta1 (TGF-beta1) promotes fibrosis by enhancing the synthesis of extracellular matrix components. The role of TGF-beta1 in promoting fibrosis in the setting of pulmonary eosinophilic granuloma is currently unknown. We used immunohistochemistry to evaluate the extent and distribution of TGF-beta1 and the extracellular matrix components type I collagen and decorin, a TGF-beta1-binding proteoglycan. Lung biopsies from 11 patients with pulmonary eosinophilic granuloma were evaluated. In biopsies with active inflammatory lesions containing Langerhans' cells, hyperplastic type 2 pneumocytes and alveolar macrophages within and surrounding the fibronodular lesions contained abundant TGF-beta1. Langerhans' cells were consistently devoid of immunoreactive TGF-beta1. Active inflammatory lesions also exhibited staining for decorin, in a loosely organized distribution. Advanced fibrotic lesions of eosinophilic granuloma, containing minimal inflammatory cells and few or no Langerhans' cells, exhibited weak or absent staining for TGF-beta1 within either hyperplastic type 2 pneumocytes or alveolar macrophages. The fibroconnective tissues of these advanced fibrotic lesions consistently revealed dense staining for decorin. Through their actions on extracellular matrix protein accumulation, TGF-beta1 and the TGF-beta1-binding proteoglycan decorin may modulate fibrotic repair accompanying pulmonary eosinophilic granuloma.
Collagen↗
Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy.
OBJECTIVE: To determine the clinical spectrum of immunosuppressive conditions and systemic corticosteroid therapy associated with the development of Pneumocystis carinii pneumonia in a consecutive series of patients without acquired immunodeficiency syndrome (AIDS). DESIGN: We retrospectively analyzed a consecutive series of 116 patients without AIDS who were assessed at Mayo Medical Center for a first episode of P. carinii pneumonia between 1985 and 1991. METHODS: Medical records were examined to determine underlying immunosuppressive disorders, premorbid corticosteroid dosage and duration of therapy, associated infections, and subsequent respiratory failure and in-hospital mortality. RESULTS: Conditions associated with a first episode of P. carinii pneumonia were hematologic malignant disorders (30.2%), organ transplantation (25.0%), inflammatory disorders (22.4%), solid tumors (12.9%), and miscellaneous conditions (9.5%). Regardless of the associated underlying disease, corticosteroids had been administered systemically in 105 patients (90.5%) within 1 month before the diagnosis of P. carinii pneumonia. The median daily corticosteroid dose was equivalent to 30 mg of prednisone; however, 25% of patients had received as little as 16 mg of prednisone daily. The median duration of corticosteroid therapy was 12 weeks before the development of pneumonia; however, P. carinii pneumonia developed after 8 weeks or less of corticosteroid therapy in 25% of these patients. Respiratory failure occurred in 43%, and in-hospital mortality was 34% for patients with P. carinii pneumonia in conditions other than AIDS. CONCLUSION: Although these results do not suggest that premorbid administration of corticosteroids is the only factor that contributes to the development of P. carinii pneumonia in these patients, they show that, in this large consecutive series, systemic corticosteroid therapy, even in moderate doses, was administered to most patients during the month preceding the onset of P. carinii pneumonia. Consideration should be given to instituting P. carinii prophylaxis (when not contra-indicated) in patients for whom prolonged systemic corticosteroid therapy is prescribed.
AIDS-Related Opportunistic Infections↗
Diagnosis of Pneumocystis carinii pneumonia: does use of only bronchoalveolar lavage suffice?
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Bronchoalveolar Lavage Fluid↗
Pneumocystis carinii glycoprotein A binds macrophage mannose receptors.
Pneumocystis carinii causes life-threatening pneumonia in patients with impaired immunity. Recent studies suggest that alveolar macrophages interact with P. carinii through macrophage mannose receptors. However, the ligand(s) on P. carinii that is recognized by these receptors has not been fully defined. P. carinii contains a major mannose-rich surface antigen complex termed glycoprotein A (gpA). It was therefore hypothesized that gpA binds directly to macrophage mannose receptors and mediates organism attachment to these phagocytes. To assess this, gpA was purified from P. carinii by continuous-elution gel electrophoresis. 125I-labeled gpA bound to alveolar macrophages in a saturable fashion. In addition, gpA binding was substantially inhibited by both alpha-mannan and EDTA, further suggesting that gpA interacts with macrophage mannose receptors. Macrophage membrane proteins capable of binding to gpA were isolated with a gpA-Sepharose column. A 165-kDa membrane-associated protein was specifically eluted from the gpA-Sepharose column with EDTA (20 mM). This protein was identified as the macrophage mannose receptor by immunoprecipitation with a polyclonal anti-mannose receptor antiserum. To further investigate the role of gpA in P. carinii-macrophage interactions, 51Cr-labeled P. carinii cells were incubated with macrophages in the presence of increasing concentrations of soluble gpA, and organism attachment was quantified. Soluble gpA (2.5 mg/dl) competitively inhibited P. carinii attachment to alveolar macrophages by 51.3% +/- 3.7% (P = 0.01). Our findings demonstrate that gpA present on P. carinii interacts directly with mannose receptors, thereby mediating organism attachment to alveolar macrophages.
Animals↗
Surfactant protein D interacts with Pneumocystis carinii and mediates organism adherence to alveolar macrophages.
Pneumocystis carinii interacts with glycoproteins present in the lower respiratory tract through its mannose-rich surface antigen complex termed gpA. Surfactant protein D (SP-D) is a recently described component of the airspace lining material that possesses a calcium-dependent lectin domain capable of interacting with glycoconjugates present on microorganisms and leukocytes. Accordingly, we evaluated the extent and localization of SP-D in the lower respiratory tract during Pneumocystis pneumonia in an immunosuppressed rat model and examined its role in modulating interaction of P. carinii with macrophages. We report that SP-D is a major component of the alveolar exudates that typify P. carinii pneumonia and is present bound to the surface of P. carinii organisms in vivo. We further demonstrate that SP-D binds to P. carinii through saccharide-mediated interactions with gpA present on the surface of the organism. Lastly, we show that SP-D augments binding of P. carinii to alveolar macrophages, but does not significantly enhance macrophage phagocytosis of the organism. The interaction of SP-D with gpA represents an additional important component of the host-parasite relationship during P. carinii pneumonia.
Animals↗
Adhesive glycoproteins in the pathogenesis of Pneumocystis carinii pneumonia: host defense or microbial offense?
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Animals↗
Drug-induced pulmonary disease.
In any febrile patient with an unexplained chest radiographic abnormality who is on medication, the possibility that the observed abnormality is drug-induced must be kept in mind. This is a significant problem in the immunocompromised host receiving chemotherapeutic agents because these agents are almost always associated with a fever, although the fever may not be daily and is usually not associated with sweats or shaking chills. The infiltrate initially can be quite focal and then unilateral, exhibiting diffuse lung disease before becoming bilateral. Thus, in its early stages, it mimics an infectious process. Unfortunately there is no diagnostic test to rule in drug-induced lung disease because it really is a condition of exclusion. Lung biopsy may be required to exclude other causes. It is also important to remember that drugs may be a factor in the immunocompetent patient who is taking medication and has a fever. It is important for the clinician to be aware of which drugs can do this.
Amiodarone↗
Surfactant protein-D modulates interaction of Pneumocystis carinii with alveolar macrophages.
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Animals↗
Comparison of neutrophil chemotactic factor release by human and rabbit alveolar macrophages in response to tannin exposure.
It is essential to determine whether the results obtained from animal models actually reflect human disease processes. Tannin is a component of cotton dust that acts as a polyclonal cell activator in vitro. Most of the effects of tannin on alveolar macrophages (AM phi) have been studied in rabbit AM phi. Therefore, we compared tannin-mediated in vitro neutrophil chemotactic factor (NCF) secretion from normal human and rabbit AM phi. For both species the NCF secretion from AM phi was dependent on tannin dose and time of exposure. The NCF released was a lipid with a molecular weight of less than 800 daltons, suggesting that it may be a metabolite of arachidonic acid. Tannin stimulation of both human and rabbit AM phi resulted in the release of 90% unmetabolized arachidonic acid derived from both phosphatidyl choline and phosphatidyl inositol membrane lipids. The NCF secreted was not leukotriene B4 or platelet-activating factor. In conclusion, tannin mediates the release of a so far undescribed NCF from resident AM phi in rabbits and human subjects that may contribute to the pathogenesis of the acute neutrophilic alveolitis associated with cotton dust inhalation. The similarity of results obtained from human and rabbit cells supports the pertinence of using rabbit cells to study tannin-mediated effects.
Animals↗
Vitronectin, fibronectin, and gp120 antibody enhance macrophage release of TNF-alpha in response to Pneumocystis carinii.
Alveolar macrophages (AMS) initiate inflammation during Pneumocystis carinii pneumonia by releasing cytokines including TNF-alpha. Recent studies suggest that macrophage responses to P. carinii are enhanced by serum opsonization, but the mechanisms of enhancement are not well defined. To determine whether macrophage release of TNF-alpha in response to P. carinii was augmented by immune opsonization, alveolar macrophages obtained from rabbits were cultured with P. carinii that had been opsonized with either nonimmune rabbit serum, immune serum generated against P. carinii, or an affinity-purified polyclonal Ab recognizing the major P. carinii surface Ag gp120. Each experiment also included organisms maintained in media alone (nonopsonized P. carinii). Opsonization of P. carinii with immune serum or gp120 Ab significantly enhanced macrophage TNF-alpha release. Interestingly, however, opsonization with nonimmune serum also increased TNF-alpha response to the organism. Because P. carinii is known to interact with the adhesive glycoproteins, vitronectin (VN) and fibronectin (FN), we hypothesized that they might also augment TNF-alpha release. Opsonization of P. carinii with VN or FN resulted in significant potentiation of macrophage TNF-alpha liberation. We further determined that VN and FN were present in increased quantities in the lower respiratory tract of patients with P. carinii pneumonia compared with normal volunteers. Additionally, VN and FN were demonstrated on the surface of freshly isolated P. carinii organisms by immunoblot analysis. Our study suggests that immune and nonimmune opsonins contribute to host defenses during P. carinii pneumonia by enhancing regional TNF-alpha release in response to the organism.
Animals↗
Vitronectin interacts with Candida albicans and augments organism attachment to the NR8383 macrophage cell line.
Candida albicans is an increasingly important cause of mucocutaneous and bloodstream infections. The potential role of circulating adhesive glycoproteins such as vitronectin (Vn) in host defense against C. albicans is currently unknown. Accordingly, we investigated the binding of plasma-derived Vn with C. albicans strain 36082. Vn specifically bound to C. albicans in a concentration-dependent fashion. Higher affinity binding sites numbered 9.8 x 10(4) sites per organism, with a dissociation constant, Kd of 3.5 x 10(-7) M. Vn binding with C. albicans was significantly inhibited by heparin, suggesting interaction of the organism with Vn's glycosaminoglycan-binding region. To further determine which molecule(s) on the fungus interacted with Vn, C. albicans components were extracted, separated by SDS and blotted with radiolabeled Vn. These studies revealed that Vn binds to a 30 kDa molecule on C. albicans. Finally, we investigated the role of Vn in promoting interaction of C. albicans with phagocytic cells. Incubation of C. albicans in the presence of Vn significantly increased binding of the organism to cultured NR8383 macrophages compared to incubations performed in the absence of Vn. These data demonstrate that C. albicans interacts with the heparin-binding domain Vn and further suggest that Vn augments organism uptake by phagocytic cells.
Amino Acid Sequence↗
Diagnosing ventilator-associated pneumonia: the role of bronchoscopy.
OBJECTIVE: To discuss the two diagnostic procedures used most frequently to obtain uncontaminated lower airway secretions during bronchoscopy. DESIGN: This article reviews the contributing risk factors of ventilator-associated pneumonia (VAP) and the recent studies that have assessed the usefulness of the protected specimen brush (PSB) and bronchoalveolar lavage (BAL) in the nonimmunocompromised host. RESULTS: A prompt, accurate diagnosis of VAP, including specific identification of the bacterial pathogen, remains a common challenge in the intensive-care unit. Standard clinical criteria are of suboptimal specificity for making decisions, including selecting antibiotic therapy. Bronchoscopic techniques of lung secretion sampling can be used in the intensive-care unit in an effort to overcome the effects of oropharyngeal contamination. The PSB and BAL, used appropriately, can help intensive-care clinicians formulate specific antimicrobial therapy. Evaluation of intracellular bacteria obtained by BAL has been reported to be useful in guiding empiric antibiotic therapy while the final results of cultures obtained with the PSB are pending. Prior antibiotic therapy, however, may confound the interpretation and clinical utility of results. CONCLUSION: Currently, for a patient taking antibiotic therapy, no reliable technique nor quantitative culture threshold exists to help in diagnosing suspected VAP or in guiding antibiotic therapy. If the clinical situation allows, antibiotic therapy should be discontinued for 48 hours; then, the PSB, BAL, protected BAL, or endobronchial aspiration should be used. These contemporary modalities, however, necessitate further clinical trials before widespread use is warranted.
Anti-Bacterial Agents↗
Candida albicans stimulates arachidonic acid liberation from alveolar macrophages through alpha-mannan and beta-glucan cell wall components.
Candida albicans is an increasingly important fungal pathogen. Alveolar macrophages respond to fungal components such as zymosan by releasing arachidonic acid (AA) and AA metabolites. However, few studies hypothesized that macrophages respond to C. albicans by releasing AA and generating AA metabolites as a consequence of interaction of mannose and beta-glucan receptors with fungal cell wall components. [14C]AA-labeled rabbit alveolar macrophages released AA following stimulation with either live or heat-killed C. albicans. High-pressure liquid chromatography analysis revealed that 55% of the AA released was metabolized via cyclooxygenase and lipoxygenase pathways. The metabolites consisted of prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha, thromboxane B2, and leukotrienes B4 and D4. We further examined the roles of alpha-mannan and beta-glucan components of C. albicans in mediating these alterations of eicosanoid metabolism. Prior work in our laboratory has shown that soluble alpha-mannan and beta-glucan inhibit macrophage mannose and beta-glucan receptors, respectively. Incubation of alveolar macrophages with soluble alpha-mannan derived from C. albicans (1 mg/ml) resulted in 49.8% +/- 2.6% inhibition of macrophage AA release during stimulation with intact C. albicans (P = 0.0001 versus control). Macrophage AA release in response to C. albicans was also inhibited to a significant but lesser degree by soluble beta-glucan (36.2% +/- 1.3%; P = 0.008 versus control). These results indicate that C. albicans stimulates macrophage AA metabolism and that these effects are partly mediated by alpha-mannan and beta-glucan constituents of the fungus.
Animals↗
Immunohistochemical localization of transforming growth factor-beta 1 in the nonnecrotizing granulomas of pulmonary sarcoidosis.
Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by the formation of nonnecrotizing granulomas in affected tissues, most notably the lungs. Granuloma healing may result in pulmonary fibrosis and respiratory impairment in some patients. Transforming growth factor-beta 1 (TGF-beta 1) is a potent cytokine that promotes fibrosis by enhancing the synthesis of extracellular matrix components, including fibronectin and the alpha 5 beta 1 fibronectin receptor. The role of TGF-beta 1 in promoting lung fibrosis in the setting of pulmonary sarcoidosis has not yet been investigated. Accordingly, we determined the extent and distribution of TGF-beta 1 in lung tissue obtained from seven patients with clinical and histologic features of pulmonary sarcoidosis. The tissue distributions of TGF-beta 1, the TGF-beta 1 binding proteoglycan decorin, fibronectin, and the alpha 5 beta 1 fibronectin receptor were assessed immunohistochemically. In all cases, the epithelioid histiocytes comprising nonnecrotizing granulomas of pulmonary sarcoidosis contained abundant TGF-beta 1. We further demonstrated decorin, fibronectin, and the alpha 5 beta 1 fibronectin receptor within nonnecrotizing granulomas and in the fibrous tissue surrounding the lesions. TGF-beta 1 staining was also observed in bronchiolar epithelial cells, hyperplastic Type II pneumocytes, and occasional alveolar macrophages. This study demonstrates enhanced tissue localization of TGF-beta 1 and related extracellular matrix proteins associated with the nonnecrotizing granulomas of pulmonary sarcoidosis. Through its actions on matrix protein synthesis, TGF-beta 1 may modulate the fibrotic repair process accompanying granuloma healing in sarcoidosis.
Adult↗