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CD8+ T cells predominate in the lungs in hypersensitivity and human immunodeficiency virus-related lymphocytic pneumonitis, but their role in the immunopathogenesis of lung disease is unknown. We have shown that in immunized mice depleted of CD4+ T cells, CD8+ T cells are recruited into the lungs in response to intratracheal antigen challenge with sheep red blood cells (SRBC) (J. Clin. Invest. 1991; 88:1244-1254) or to pulmonary infection with Pneumocystis carinii (Am. J. Respir. Cell Mol. Biol. 1991; 5:186-197), suggesting that recruitment of CD8+ T cells does not depend on CD4+ T cell-derived signals. Because CD8+ T cells themselves produce a variety of chemotactic and immunoregulatory cytokines, CD8+ T cells may be important participants in, and modulators of, pulmonary immune responses. To test this hypothesis, we examined the effects of CD8+ T cell depletion on the generation of a pulmonary immune response in vivo. We monitored the recruitment of mononuclear cells into lungs in the absence of CD8-dependent signals and measured the duration of pulmonary inflammation in the absence of suppressor CD8+ T cells. Primed mice were treated with anti-CD8 monoclonal antibody to deplete CD8+ T cells and subsequently were challenged intratracheally with 5 x 10(8) SRBC. At various times after challenge, total and differential cell counts and lymphocyte phenotypes were measured in bronchoalveolar lavage fluid by flow cytometry and lungs were scored histologically. We found that depletion of CD8+ T cells neither decreased recruitment of immune and inflammatory cells nor prolonged the pulmonary immune response.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Jul
PMID:Pulmonary lymphocyte recruitment: depletion of CD8+ T cells does not impair the pulmonary immune response to intratracheal antigen. 833 79

B lymphocytes are crucial participants in pulmonary immune defense. However, excess local antibody production is associated with accelerated lung destruction in several types of lung disease. The purpose of the current study was to study the potential role of alveolar macrophages (AM) in the local regulation of immunoglobulin (Ig) production in the lung in response to a direct B cell mitogen, Staphylococcus aureus Cowan strain (SAC). AM, when added to peripheral blood mononuclear cells, caused a dose-dependent inhibition of IgG and IgM, while not affecting IgA production in response to SAC. The mechanism of the AM-induced inhibition included both membrane-bound and soluble signals. The inhibition was not abrogated by indocin and catalase, or reversed by blocking antibodies to transforming growth factor-beta or interferon-gamma. Mononuclear cells isolated from human lung parenchyma displayed a reduced response to SAC compared with blood cells. However, depletion of macrophages from the parenchymal cells was associated with a restoration of IgG production in response to SAC. The results demonstrate that AM inhibit B cell responses to direct B cell mitogen and suggest that the effect of AM is selective for IgM and IgG.
Am J Respir Cell Mol Biol 1993 Aug
PMID:Human alveolar macrophages inhibit immunoglobulin production in response to direct B cell mitogen. 833 83

The role of pro-inflammatory cytokines in an animal model of allergic lung disease was examined by use of an interleukin-1 receptor antagonist (IL-1ra) and a specific bioassay for tumor necrosis factor (TNF). Ovalbumin-sensitized guinea pigs exhibit a marked bronchial hyperreactivity (assessed by airway responsiveness to intravenous histamine) and pulmonary eosinophil accumulation (assessed by bronchoalveolar lavage) 24 h after challenge with aerosolized antigen. Exposure of animals to an aerosol of IL-1ra (50 micrograms over 30 min) immediately before antigen challenge resulted in a marked protection against bronchial hyperreactivity and pulmonary eosinophil accumulation compared with IL-1ra vehicle-pretreated animals. Additionally, we report for the first time generation of TNF bioactivity in the bronchoalveolar lavage of antigen-challenged animals, which was significantly reduced in animals exposed to aerosolized IL-1ra before challenge. These studies point to a key role for the cytokines IL-1 and possibly TNF in the pulmonary changes observed during allergic airway disease.
Am J Respir Cell Mol Biol 1993 Apr
PMID:Cytokines contribute to airway dysfunction in antigen-challenged guinea pigs: inhibition of airway hyperreactivity, pulmonary eosinophil accumulation, and tumor necrosis factor generation by pretreatment with an interleukin-1 receptor antagonist. 847 30

Previous attempts to culture mouse alveolar type II (ATII) cells have been hampered by limited purity and cell recovery. We have now obtained culturable ATII cells from female C57BL/6 mice at a purity of 92% +/- 3 (mean +/- SD; n = 20), with viabilities of 96% +/- 2 and total yields of 5.1 +/- 0.7 X 10(6) cells per mouse. Crude lung cell suspensions were prepared by intratracheal instillation of Dispase and agarose followed by mechanical disaggregation of the lungs. Crude cell suspensions were purified by negative selection using a biotinylated-antibody, streptavidin-coated biomagnetic particle system. Cell purities were determined by Pap staining and confirmed ultrastructurally. Purified ATII cells were cultured on fibronectin-coated chamber slides and maintained for up to 5 days in DMEM with 10% fetal bovine serum. Cultures exhibited minimal contamination by Clara cells, mesenchymal cells, or endothelial cells, and the epithelial nature of the cultures was confirmed by positive cytokeratin staining in at least 97% of the cells through day 5. Day 3 cultures demonstrated osmium tetroxide/tannic acid-stained granules consistent with lamellar bodies in 76% +/- 3.6 of the cells. The cultures displayed features distinct from those previously described for adult rat ATII cells, including irregularly-shaped cells and the formation of numerous cytoplasmic projections in direct contact with other cells. These studies indicate that excellent yields of highly purified, culturable ATII cells can be obtained from genetically defined mice. These techniques may provide powerful new models for the study of parenchymal lung disease in vitro.
Am J Respir Cell Mol Biol 1996 Apr
PMID:Isolation and primary culture of murine alveolar type II cells. 860 Sep 33

Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease of unknown etiology in which the alveoli and terminal bronchioles of the lung fill with large amounts of surfactant-rich lipoproteinaceous materials. Its major pathologic manifestations are a small number of normal tubular myelin structures and an unusual abundance of multilamellated structures. Since surfactant protein A (SP-A) plays an important role in surfactant phospholipid homeostasis, we investigated the structural features of SP-A oligomers (alveolar proteinosis protein, APP) accumulating in the alveoli of individuals with PAP, and examined the abilities of APP to interact with lipids. Analysis of APP by Bio Gel A15m column chromatography revealed that it was composed of two protein peaks, one of which (APP-I) eluted at the position near that of blue dextran whereas the other (APP-II) eluted far behind blue dextran but ahead of thyroglobulin. These populations of APP showed almost identical amino acid compositions. Electron microscopic observations of APP molecules using the rotary shadow technique revealed that APP-II was observed as hexameric particles, presumably consisting mainly of octadecamers whose diameter was approximately 30 nm. The population seen for APP-II was similar to that seen for SP-A from healthy individuals. In contrast, APP-I was observed as multimerized larger aggregates whose diameter appeared to be about 70 to 90 nm. Both APP-I and APP-II retained the abilities to bind dipalmitoylphosphatidylcholine (DPPC). They also induced phospholipid vesicle aggregation in a concentration-dependent manner. The maximal turbidity for light scattering induced by APP-I and APP-II was almost equivalent when analyzed as a function of molar concentration. In vitro reconstitution experiments with porcine surfactant protein B (SP-B) and phospholipids revealed that the multilamellated membranes in structures formed from APP-I consisted of several layers of doubled unit membranes. APP-I failed to form tubular myelin structures. In contrast, APP-II formed well-formed lattice structures seen in tubular myelin. From these data we conclude that there exists an abnormal multimerized form of SP-A oligomer in the alveoli of patients with PAP, and that this unusual subpopulation of SP-A oligomer exhibits abnormal function on phospholipid membrane organization.
Am J Respir Cell Mol Biol 1996 Jun
PMID:Surfactant protein A accumulating in the alveoli of patients with pulmonary alveolar proteinosis: oligomeric structure and interaction with lipids. 865 89

A central factor in the pathogenesis of inflammatory and fibrotic lung disease (adult respiratory distress syndrome, sarcoidosis, idiopathic pulmonary fibrosis) is the locally elevated number of alveolar macrophages (AM). An elevation in the production rate of AM, chemoattraction and differentiation of monocytes, or a diminution in the death rate might be underlying mechanisms. The aim of the present study was to investigate the modulatory role of endotoxin and cytokines on the death rate of human AM. Lipopolysaccharide (LPS) treatment resulted in a 4-fold increase (7.6 to 30.2%) of AM death. AM death was apoptotic as assessed by in situ DNA end labeling (ISDE), transmission electron microscopy, DNA gel electrophoresis, fluorometry of fragmented DNA, and an ELISA specific for histone-associated DNA fragments. Among the different bacterial cell wall components tested, LPS was the only inducer of apoptosis in human AM. None of the tested cytokines (interleukin-1 beta [IL-1 beta], IL-4, IL-6, IL-10, tumor necrosis factor-alpha [TNF-alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], macrophage colony-stimulating factor [M-CSF], granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) was capable of enhancing the spontaneous rate of apoptosis. However, LPS-induced apoptosis was significantly enhanced by the macrophage-activating cytokine IFN-gamma, and reduced by the macrophage-deactivating cytokines IL-4, IL-10, and TGF-beta.
Am J Respir Cell Mol Biol 1996 Jul
PMID:Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines. 867 23

Viral infection in children commonly causes acute lung disease leading to respiratory decompensation requiring intensive supportive therapy. Definitive diagnosis of the causative virus may be difficult, relying on serologic data since viral cultures are frequently negative; lung biopsy may be necessary to increase the diagnostic yield. The objective of this study was to develop a rapid and sensitive diagnostic method using the polymerase chain reaction (PCR). Analyzing Formalin-fixed lung tissue from autopsies of 32 patients with pneumonitis in whom cultures, serology, and histopathology results were blinded to the investigators, and 10 negative control samples, PCR was performed for cytomegalovirus, adenovirus, enteroviruses, herpes simplex virus, and Epstein-Barr virus. Among the 32 affected specimens, 7 were culture-positive for a specific virus in the lung; 6/7 of these were PCR-positive for the identical virus. In the culture-positive specimen not PCR amplified, influenza B was the cultured agent, but this virus was not evaluated by PCR. In the remaining 25 samples which were culture-negative, 11 were PCR-positive. All 10 negative controls were negative by PCR. Three specimens with CMV inclusions but culture-negative were also negative by PCR. We conclude that PCR is sensitive and accurate in the evaluation of lung tissue for viral pneumonitis.
Biochem Mol Med 1996 Jun
PMID:PCR diagnosis of viral pneumonitis from fixed-lung tissue in children. 880 48

Limited information is available about the pathogenesis of acquired immune deficiency syndrome (AIDS)-associated idiopathic interstitial pneumonitis, a common noninfectious complication of human immunodeficiency virus (HIV) infection. Infection of C57B1/6 mice with LP-BM5 retrovirus, a murine model of AIDS, leads to development of a diffuse interstitial pneumonitis that displays many features of human AIDS-associated interstitial pneumonitis. To further characterize the cellular and molecular features of this lung disease, the temporal development of cellular infiltration, cytokine expression, and virus replication were evaluated in lung tissue of virus-infected mice. Persistent expression of viral RNA was detectable in lungs as early as 1 wk after infection. Infiltration of the lungs by CD4+ and CD8+ T cells, by IgG+ and IgA+ B cells, and by macrophages was observed by 4 wk after infection and continued through 8 wk of infection. Histologically, cellular infiltration was most pronounced in peribronchial and perivascular regions, whereas inflammation of alveolar septae and alveolar spaces was minimal. In contrast to normals, T cells from infected lungs were immunodeficient in that they failed to proliferate in response to the mitogen concanavalin A (ConA). However, evaluation of cytokine mRNA expression by interstitial lung lymphoid cells indicated that cells from infected lungs were chronically activated, in that elevated expression of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) was observed throughout the course of infection. Similarly, expression by interstitial lung lymphoid cells of mRNA for the proinflammatory cytokine IL-1 and the fibrogenic cytokine transforming growth factor-beta (TGF-beta) was also increased following infection. These results indicate that retrovirus-induced immunodeficiency in mice is associated with infiltration and chronic activation of lymphoid cells in the lungs. Furthermore, simultaneous expression of IL-10, IFN-gamma, and TGF-beta suggests that cytokine-expressing cells in infected lungs may be unresponsive to inhibitory and antiinflammatory effects of IL-10 and/or TGF-beta, thus contributing to chronicity of inflammation in this disorder.
Am J Respir Cell Mol Biol 1997 Feb
PMID:Pulmonary lymphoid cell activation and cytokine expression in murine AIDS-associated interstitial pneumonitis. 903 22

Human trials for the treatment of cystic fibrosis lung disease with adenoviral vectors have been complicated by acute inflammatory reactions of unknown etiology. Because replicating respiratory viruses can potentiate tachykinin-mediated neurogenic inflammatory responses in airways, we studied whether the endotracheal administration of a replication-deficient adenoviral vector potentiated this response. The vector Ad5CMVLacZ was administered endotracheally to rats and the leakage of Evans blue dye was used to measure the capsaicin-induced neurogenic albumin extravasation. These studies show that neurogenic albumin extravasation is significantly potentiated in the airways of rats after administration of Ad5CMVLacZ. This inflammatory response can be blocked by selective antagonists of the substance P receptor or by glucocorticoids. Therefore, (1) the acute airway inflammation observed in patients after exposure to adenoviral vectors may exhibit a neurogenic component, which can be blocked pharmacologically, and (2) preclinical adenoviral vector safety studies of other organs innervated by the tachykinin system, e.g., coronary arteries and gastrointestinal tract, should include assessment of neurogenic inflammation.
Am J Respir Cell Mol Biol 1997 Mar
PMID:Replication-deficient adenoviral vector for gene transfer potentiates airway neurogenic inflammation. 907 Jun 9

We investigated whether intraalveolar inflammatory cells such as alveolar macrophages or lymphocytes produced the gene product of a type-C human endogenous retrovirus (HERV), HERV-E 4-1, which might initiate an immune response resulting in interstitial lung disease. We evaluated HERV-E 4-1 Env protein production by bronchoalveolar lavage fluid (BALF) cells and PBL in 109 patients with sarcoidosis, idiopathic pulmonary fibrosis (IPF), lung cancer, and rheumatoid lung disease as well as 26 normal control individuals. Production of HERV-E 4-1 Env protein by alveolar macrophages was observed using indirect immunofluorescence in 3 IPF patients and 3 sarcoidosis patients (6/135). No peripheral blood lymphocytes showed HERV-E 4-1 Env protein production. Antibodies to HERV-E 4-1 Env protein were detected in the BALF of all six patients by immunoblot analysis, while none of the normal control individuals showed HERV-E 4-1 Env protein antibody in the BALF. All examined BALF cells showed HERV-E 4-1 env mRNA transcript expression by reverse transcription-polymerase chain reaction. No significant influence of point mutation or DNA polymorphism on HERV-E 4-1 Env protein production was recognized. In conclusion, local production of HERV-E 4-1 Env protein and defective tolerance of HERV gene products with resultant antibody production may contribute to the pathogenesis of IPF or sarcoidosis in some patients.
Am J Respir Cell Mol Biol 1997 Apr
PMID:Alveolar macrophages produce the Env protein of a human endogenous retrovirus, HERV-E 4-1, in a subgroup of interstitial lung diseases. 911 54


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