T lymphocyte phenotypic profile in lung segments affected by cavitary and non-cavitary tuberculosis

Clinical manifestations of pulmonary tuberculosis (TB) may depend on a complex interaction between the host and the pathogen. Clinical outcomes of pulmonary tuberculosis are variable, ranging from asymptomatic lifelong infection to parenchymal lung destruction, resulting in cavitary lesions. To investigate the hypothesis that local cellular immune response may affect presentation and outcome in tuberculosis, we performed bronchoalveolar lavage (BAL) in lung segments affected by cavitary and non-cavitary tuberculosis. We then correlated the type of cellular response at the level of the involved lung segments with clinical evolution in terms of cavity formation. We found alveolar lymphocytosis in patients with both cavitary and non-cavitary pulmonary tuberculosis, with increased CD4+ lymphocytes in patients with non-cavitary pulmonary tuberculosis. A predominant Th1 immune response has been observed in non-cavitary patients, while cavitary involved segments exhibit the presence of Th2 lymphocyte subsets. These data, while confirming the importance of Th1-type CD4+ cells and IFN-gamma in effective cellular immunity in active pulmonary tuberculosis, also suggest that the presence of Th2 lymphocytes may contribute to tissue necrosis phenomena associated with cavitary evolution of pulmonary tuberculosis. Our observations indicate the importance of the type of local immune response at the site of disease in the development of different clinical characteristics and outcome in pulmonary tuberculosis.     

Transient gene transfer of non-ELR chemokines to rodent lung induces mononuclear cell accumulation and activation.

The in vivo function of the CXC chemokines interferon-inducible protein-10 (IP-10) and monokine induced by gamma (MIG) was examined using replication-deficient adenoviral vectors expressing human IP-10 (AdIP-10) or murine MIG (AdMIG). Intratracheal and intranasal administration of AdIP-10 or AdMIG into rats and mice produced transient chemokine overexpression from the bronchial epithelium. IP-10 concentrations in the bronchoalveolar lavage fluid (BAL) of AdIP-10-treated animals showed peak expression (>2 ng/ml) 24-48 h after AdIP-10 administration. Dramatic transient increases in BAL cellularity (macrophages, monocytes, lymphocytes, and neutrophils) were observed in AdIP-10-treated and AdMIG-treated animals, and histologic examination of AdIP-10-treated lungs revealed transient infiltrations of mononuclear cells primarily localized around the bronchus and extending throughout the lung parenchyma. However, in immunocomprised SCID mice, only increases in natural killer cell populations were detected in BAL following AdIP-10 intranasal administration, indicating that monocyte/macrophage and neutrophil accumulation was likely the result of factors released from activated lymphocytes.     

Treatment of monocytes with interleukin (IL)-12 plus IL-18 stimulates survival, differentiation and the production of CXC chemokine ligands (CXCL)8, CXCL9 and CXCL10

During inflammation, interleukin (IL)-12 and IL-18 are produced by macrophages and other cell types such as neutrophils (IL-12), keratinocytes and damaged endothelial cells (IL-18). To explore the role of IL-12 and IL-18 in inflammatory innate immune responses we investigated their impact on human peripheral blood monocytes and mature bronchoalveolar lavage (BAL) macrophages. IL-12 and IL-18 together, but not alone, prevented spontaneous apoptosis of cultured monocytes, promoted monocyte clustering and subsequent differentiation into macrophages. These morphological changes were accompanied by increased secretion of CXC chemokine ligands (CXCL)9, CXCL10 (up to 100-fold, P < 0.001) and CXCL8 (up to 10-fold, P < 0.001) but not CCL3, CCL4 or CCL5. Mature macrophages (from BALs) expressed high basal levels of CXCL8, that were no modified upon stimulation with IL-12 and IL-18. In contrast, the basal production of CXCL9 and CXCL10 by BALs was increased by 10-fold (P < 0.001) in the presence of either IL-12 or IL-18 alone and by 50-fold in the presence of both cytokines. In conclusion, our results indicate a relevant role for IL-12 and IL-18 in the activation and resolution of inflammatory immune responses, by increasing the survival of monocytes and by inducing the production of chemokines. In particular, those that may regulate angiogenesis and promote the recruitment of monocytes, activated T cells (CXCL9 and CXCL10) and granulocytes (CXCL8).     

Neutrophil chemotactic factor in lung injury produced by immune complexes

Our previous study demonstrated increased levels of C5a des Arg and increased numbers of neutrophils in bronchoalveolar lavage (BAL) fluids of patients acutely ill with hypersensitivity pneumonitis (HP), suggesting that complement fragments activated by immune complexes (IC) play a role in the early stage of disease. The present study was undertaken to clarify the mechanisms involved in lung injury produced by IC formed in the airway. Sequential changes of neutrophils and neutrophil chemotactic activities (NCF) in BAL fluids were evaluated in guinea-pigs injected intratracheally with preformed IC. Our results were as follows: 1) There was an increased number of neutrophils in BAL cells within 48 hours of the intratracheal injection with preformed IC reaching a peak at 24 hours postinjection. 2) NCF in BAL fluids were potent at 2-6 hours postinjection and preceded an increase of neutrophils in BAL cells, indicating that NCF play a role in the accumulation of neutrophils in the lung. 3) A consequent increase of alveolar macrophages and macrophage chemotactic activities (MCF) in BAL fluids was observed but to a lesser extent. 4) Pretreatment with cobra venom factor of guinea-pigs reduced the increase of BAL cells, especially neutrophils and NCF to approximately 60% of comparable results, suggesting that complement fragments play a role in IC mediated lung injury.     

Antiretroviral treatment reverses HIV-induced reduction in the expression of surface antigens on alveolar macrophages in AIDS patients.

MoAbs and immunoperoxidase methods were used to identify antigen-presenting and phagocytic cells and to assess expression of HLA-DR molecules on cells obtained by bronchoalveolar lavage (BAL) from 33 AIDS patients and nine normal volunteers. In 17 patients, not receiving antiretroviral therapy, the expression of HLA-DR molecules (MoAb RFDR1) as well as the percentages of cells expressing RFD1 marker for antigen-presenting cells and RFD7 marker for mature phagocytes were significantly reduced. However, in BAL obtained after commencing treatment with zidovudine (AZT) in 21 patients or with 2',3'-dideoxyinosine (DDI) in five patients, the expression of the markers studied was found to have returned to levels of expression seen in normal lavages. The changes observed were clearly associated with antiretroviral treatment and did not correlate with applications of other drugs, blood CD4 counts or presence of infectious organisms in BAL fluid. As the alterations in the expression of HLA-DR molecules and RFD1 marker on macrophages have been shown to be associated with functional capacities of these cells, the reversal of impaired expression of phenotypic markers on alveolar macrophages in AIDS patients by AZT and DDI signifies an important ability of these drugs to modify immune reactivity and emphasizes the need to monitor such functions in HIV disease.     

Human rhinovirus induces robust IP-10 release by monocytic cells, which is independent of viral replication but linked to type I interferon receptor ligation and STAT1 activation

Human rhinovirus (HRV)-induced respiratory infections are associated with elevated levels of IFN-gamma-inducible protein 10 (IP-10), which is an enhancer of T lymphocyte chemotaxis and correlates with symptom severity and T lymphocyte number. Increased IP-10 expression is exhibited by airway epithelial cells following ex vivo HRV challenge and requires intracellular viral replication; however, there are conflicting reports regarding the necessity of type I IFN receptor ligation for IP-10 expression. Furthermore, the involvement of resident airway immune cells, predominantly bronchoalveolar macrophages, in contributing to HRV-stimulated IP-10 elaboration remains unclear. In this regard, our findings demonstrate that ex vivo exposure of human peripheral blood monocytes and bronchoalveolar macrophages (monocytic cells) to native or replication-defective HRV serotype 16 (HRV16) resulted in similarly robust levels of IP-10 release, which occurred in a time- and dose-dependent manner. Furthermore, HRV16 induced a significant increase in type I IFN (IFN-alpha) release and STAT1 phosphorylation in monocytes. Neutralization of the type I IFN receptor and inhibition of JAK or p38 kinase activity strongly attenuated HRV16-stimulated STAT1 phosphorylation and IP-10 release. Thus, this work supports a model, wherein HRV16-induced IP-10 release by monocytic cells is modulated via autocrine/paracrine action of type I IFNs and subsequent JAK/STAT pathway activity. Our findings demonstrating robust activation of monocytic cells in response to native and/or replication-defective HRV16 challenge represent the first evidence indicating a mechanistic disparity in the activation of macrophages when compared with epithelial cells and suggest that macrophages likely contribute to cytokine elaboration following HRV challenge in vivo.     

Alveolar macrophages in AIDS patients: increased spontaneous tumour necrosis factor-alpha production in Pneumocystis carinii pneumonia.

In order to assess the role of alveolar macrophages and their products in the control of Pneumocystis carinii pneumonia (PCP) and other infections in AIDS, bronchoalveolar lavage cells and peripheral blood mononuclear cells from HIV-positive AIDS/ARC patients (with and without PCP) and HIV-negative patients were counted and cultured in vitro; spontaneous and LPS-induced tumour necrosis factor-alpha (TNF-alpha) production was measured. Markedly increased spontaneous TNF-alpha production by alveolar macrophages and, to a lesser extent, peripheral blood monocytes was found in HIV-positive patients with active PCP but not in patients without the infection. Higher TNF production was associated with lower counts of Pneumocystis in the bronchoalveolar lavage fluid. These results suggest that TNF-alpha production by macrophages may play an important role in the control of Pn. carinii infection in AIDS.     

Lowered responsiveness of bronchoalveolar lavage T lymphocytes in hypersensitivity pneumonitis.

We previously reported that Trichosporon cutaneum was the major causative antigen of summer-type hypersensitivity pneumonitis (HP) in Japan. In summer-type HP patients, we noticed that the proliferative responses of bronchoalveolar lavage (BAL) lymphocytes to phytohemagglutinin (PHA) and concanavalin A were significantly lower than those of the peripheral blood lymphocytes of the same patients. It was shown in this study that the low response of BAL lymphocytes was due to an intrinsic lowering of the responsiveness of the T cells. Results of the mixed culture experiments, in which the responses to mitogens of BAL and peripheral blood T cells mixed with either alveolar macrophages or blood monocytes were compared, indicated that the decreased proliferative response was due neither to the suppressive effect nor to defects in accessory function of the alveolar macrophages. BAL T cells did not act as suppressor cells when they were added to the culture of peripheral T cells. The decreased proliferative response was not due to the dominance of CD8+ T cells frequently seen in BAL cells of HP patients, because both CD4+ and CD8+ T cells separated from BAL cells of HP patients showed lower responsiveness than those of peripheral blood T cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo collagenase-2 (MMP-8) expression by human bronchial epithelial cells and monocytes/macrophages in bronchiectasis

The purpose of this study was to determine whether other cellular sources than neutrophils can express matrix metalloproteinase (MMP)-8 protein and mRNA in bronchiectatic (BE) lung. The molecular forms of MMP-8 in the BE bronchoalveolar lavage fluid (BALF) and healthy control BALF were analysed by western immunoblotting. MMP-8 expression was demonstrated by immunohistochemistry and in situ hybridization in BE lung tissue and by immunohistochemistry in control lung tissue. In the BE BALF, different MMP-8 species were detected: 70-80 kD MMP-8 apparently of polymorphonuclear leukocyte (PMN) origin and also 40-60 kD MMP-8 from non-PMN cellular sources, such as bronchial epithelial cells, glandular cells or monocytes/macrophages. Both of these MMP-8 species were elevated and converted to a significant extent to activated forms in BE BALF compared with healthy control BALF. The levels of high molecular weight (>80 kD) MMP-8 complexes, evidently representing MMP-8 trapped by endogenous MMP inhibitors and/or MMP-8 dimers, were significantly elevated in BE BALF compared with healthy control BALF. In BE lung tissue, the MMP-8 protein and mRNA expression was found in bronchial ciliated epithelial cells, glandular cells, neutrophils, and monocytes/macrophages infiltrating the bronchial epithelial area. Minimal MMP-8 expression was observed in neutrophils, monocytes/macrophages, and epithelial cells in control lung tissues. In this study, new potential cellular sources have been demonstrated for MMP-8 in the inflamed lung. MMP-8 from multiple cellular sources, including inflamed lung epithelium, was activated to a significant extent in the BE BALF, indicating a major role for MMP-8 in the destruction of lung and bronchial tissues.     

Analysis of bronchoalveolar lavage in allergic bronchopulmonary aspergillosis: divergent responses of antigen-specific antibodies and total IgE

Bronchoalveolar lavage (BAL) was performed in eight patients with allergic bronchopulmonary aspergillosis (ABPA) at a time when chest roentgeongraphy did not reveal an infiltrate, and respiratory status was stable. BAL was tolerated well by all patients with only one patient experiencing mild wheezing. BAL fluid recovery averaged 40%, and total cells/lavage were 22.3 x 10(6) (range 3.5 to 49.5 x 10(6)). Cell viability, as determined by trypan blue exclusion, averaged 48% (range 34% to 60%). Mean values for cellular elements were macrophages, 62%; epithelial cells, 12%; lymphocytes, 16%; neutrophils (PMN), 4%; and eosinophils, 6%. Isotypic antibodies to Aspergillus fumigatus (Af) in BAL and serum were detected by an amplified indirect ELISA. Antibodies to Af in BAL expressed as optical density/albumin (milligrams per milliliter) were compared to BAL from six nonatopic patients. IgE-Af and IgA-Af in BAL were elevated in patients with ABPA compared with six nonatopic patients. The ratios of Ig-Af in BAL to peripheral blood in patients with ABPA were 48 (range 18 to 75) for IgE-Af, 96 (range 37 to 159) for IgA-Af, and 0.94 (range 0.24 to 1.40) for IgG-Af, suggesting local production of IgE-Af and IgA-Af in the bronchoalveolar compartment. Total serum IgE correlated directly with IgE-Af in BAL (rs = 0.67; p less than 0.02). However, the ratio of total BAL IgE/albumin divided by total serum IgE/albumin was 0.93 +/- 0.94, suggesting that the bronchoalveolar compartment is not the source of the significant elevations in total serum IgE in ABPA.     

Immunomodulation in mineral dust-exposed lungs: stimulatory effect and interleukin-1 release by neutrophils from quartz-elicited alveolitis.

Quartz deposition in the rat lung causes an intense and persistent neutrophil alveolitis leading to parenchymal fibrosis. Bronchoalveolar leucocytes (BAL) from quartz-exposed rat lungs were studied for their effects on splenic lymphocyte proliferation; titanium dioxide (TiO2) was used as a control, non-fibrogenic dust. Seven days after the intratracheal instillation of 1 mg of quartz or TiO2 suspended in phosphate-buffered saline (PBS), BAL were recovered by lavage; the effect of PBS alone was also studied. TiO2-elicited BAL (macrophages greater than 98%) inhibited splenocytes responding to suboptimal phytohaemagglutinin (PHA) more than PBS-elicited BAL (macrophages greater than 98%); the effect was dependent on the BAL:splenic lymphocyte ratio. Quartz-elicited whole BAL (macrophages 49%, neutrophils 51%), and an alveolar macrophage-enriched population with purity of 87% separated from it, were less inhibitory to splenocyte mitogenesis than PBS-elicited BAL. A neutrophil-enriched population, with a purity of 80%, markedly enhanced splenocyte response to PHA. In addition, whole quartz BAL and the macrophage-enriched population obtained from it enhanced the mitogenesis of T cell-enriched lymphocytes at a much lower BAL:lymphocyte ratio. The neutrophil-enriched quartz BAL enhanced mitogenesis substantially more than the whole or macrophage-enriched population from quartz-exposed lung. Supernatants from normal macrophages, PBS BAL, TiO2 BAL, quartz BAL and both alveolar macrophage and neutrophil-enriched quartz populations were assessed for interleukin-1 (IL-1) activity. Quartz-BAL, quartz macrophages and quartz neutrophils all produced significantly higher IL-1 levels than PBS BAL; the supernatants from quartz neutrophils, however, showed the highest IL-1 activity. These findings suggest that quartz-elicited bronchoalveolar leukocytes, especially neutrophils, enhance lymphocyte proliferation and that increased IL-1 secretion by these cells is likely to be the effector molecule involved. These findings have important implications for immune response in mineral dust-stimulated lung and for inflammatory lung disease in general.     

Bronchoalveolar lavage improves diagnostic accuracy in patients with diffuse lung disease

Bronchoalveolar lavage (BAL) is an established diagnostic tool in diffuse parenchyma lung disease. The objective of the present study was designed to investigate whether immunophenotyping affects BAL results and improves diagnostic accuracy. BAL from 61 patients was included in the study. The patients were also submitted to transbronchial biopsy, with a final diagnosis of granulomatous disease [tuberculosis (TB), n = 20; sarcoidosis (SARC), n = 3; and hypersensitivity pneumonitis (HP), n = 4]; idiopathic interstitial pneumonias (IIPs) [idiopathic pulmonary fibrosis (IPF), n = 9; organizing pneumonia (OP), n = 17]; and lung cancer (LC), n = 8. Immunohistochemistry and histomorphometry were used to identify and quantify type 1 and type 2 alveolar epithelial cells, macrophages, CD3+T‐cells, CD4+T‐cells, CD8+T‐cells, and CD20+B‐cells in BAL. These markers were correlated with a database and pulmonary function tests. The cellular, inflammatory, and immune components of BAL varied among the diagnostic groups and were negatively correlated with age and smoking history. An increased quantity of lymphocyte surface markers CD3 (P < 0.05) and CD20 (P = 0.01) was seen in IIPs. Patients with a pattern of OP had a higher proportion of type 2 alveolar epithelial cells; patients with SARC had a higher density of CD20+B‐cells and CD4+T‐helper cells; and patients with HP had a higher proportion of CD8+T‐cytotoxic cells. A positive association was found between the density of type I alveolar epithelial cells and forced vital capacity. The immunophenotyping affects the cellular, inflammatory, or immune constituents of BAL and improved the diagnostic accuracy in diffuse parenchymal lung disease. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Inflammatory biomarkers in airways of patients with severe asthma compared with non-severe asthma

Background About 5–10% of patients with asthma suffer from poorly-controlled disease despite corticosteroid (CS) therapy.
Objective We determined whether there were any differences in inflammatory biomarkers between severe and non-severe asthma patients.
Methods Nineteen severe and 20 non-severe asthma patients were recruited and underwent collection of induced sputum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies.
Results Biopsy results showed no differences in eosinophils (major basic protein positive), neutrophils, macrophages, T cells and mast cells in the bronchial submucosa. However, subbasement membrane (SBM) thickness and smooth muscle area were increased in the biopsies. No significant differences were observed in the induced sputum inflammatory cells. In BAL fluid, there was a significant increase in neutrophils but a significant decrease in macrophages. Eosinophil counts were non-significantly increased threefold in both sputum and BAL in severe asthma. Levels of IL-8 and IL-13 in sputum supernatants were similar in both groups of asthma patients. There was a significant inverse correlation between post-bronchodilator forced expiratory volume in 1 s and provocative concentration of methacholine causing a 20% fall in FEV₁ with SBM thickness.
Conclusion Differences in inflammatory cells were observed mainly in terms of increased neutrophils and reduction in macrophage numbers in BAL fluid with a trend towards increased eosinophils in severe asthma compared with non-severe asthma. However, the most notable features are the increase in features of airway wall remodelling of SBM thickness and smooth muscle area.     

Increased release of free oxygen radicals by phagocytosing and nonphagocytosing cells from patients with active pulmonary sarcoidosis as revealed by luminol-dependent chemiluminescence

Summary Oxidative metabolism in phagocytes such as granulocytes, monocytes, and alveolar macrophages is becoming of increasing interest in efforts to determine the pathogenetic mechanisms in diseases related to tissue damage, e.g., sarcoidosis. The release of free oxygen radicals is dependent on the activation of the oxidative metabolism and can be measured by means of chemiluminescence. Basic luminol-dependent chemiluminescence released by monocytes and alveolar macrophages from 12 patients with untreated pulmonary sarcoidosis stage II was increased (p<0.01) compared with 12 control subjects. A less distinct difference could be observed in the chemiluminescence response of granulocytes (P<0.05). After stimulation with zymosan, alveolar macrophages and monocytes (P<0.01) as well as granulocytes (P<0.05) had an enhanced luminol-dependent chemiluminescence compared with the control group. Emission of chemiluminescence by alveolar macrophages was considerably lower than that of granulocytes and monocytes.No significant correlation could be demonstrated between chemiluminescence response of granulocytes and monocytes and cellular markers of sarcoidotic activity such as lymphocytosis in bronchoalveolar lavage and T-helper/T-suppressor ratio in the lavage fluid. In contrast to that, a significant correlation (P<0.01) could be observed both between nonstimulated chemiluminescence and stimulated chemiluminescence and lymphocytosis and T-helper/T-suppressor ratio in bronchoalveolar lavage.Enhanced chemiluminescence may indicate inflammatory activation in pulmonary sarcoidosis.Abbreviations BAL bronchoalveolar lavage     

Ultrastructural study of expression of adhesion molecules between blood monocytes and alveolar macrophages from patients with pulmonary sarcoidosis

Pulmonary sarcoidosis is a chronic inflammatory disorder characterized by the presence of activated T cells and alveolar macrophages at sites of inflammation. These cells are recovered from bronchoalveolar lavage (BAL) from sarcoid patients in order to evaluate the expression of various markers on cell surfaces that should determine the diagnosis in sarcoidosis. In this work we compared the expression of VLA-4, VLA-5, Mac-1, ICAM-1 and VCAM- 1 adhesion molecules, at ultrastructural level, between blood monocytes and alveolar macrophages obtained from BAL, from patients with pulmonary sarcoidosis. Cells obtained from blood and BAL were fixed, embedded in LRWhite and then ultrathin sections were incubated with monoclonal antibodies against VLA-4, VLA-5, Mac-1, ICAM-1 and VCAM-1. The results showed a more evident labelling of all adhesion molecules on alveolar macrophages when compared to blood monocytes. The labelling was seen at cell surface, at cytoplasm and small vacuoles. The differences on adhesion molecule distributions from blood monocytes to alveolar macrophages suggest that changes in the expression of these molecules occur during pulmonary inflammatory response. Lymphocytes from BAL or blood had a weak label for these molecules.     

APOPTOSIS OF HUMAN MONOCYTES/MACROPHAGES IN MYCOBACTERIUM TUBERCULOSIS INFECTION

Tuberculosis (TB) is still a major health problem, both as a single disease entity and as a cofactor in AIDS. The interaction between macrophage and Mycobacterium tuberculosis (MTB) is a critical step in the establishment of an early chronic infection. This study analyses the capacity of MTB to induce apoptosis in cells obtained by broncho-alveolar lavage (BAL) from patients with reactive pulmonary tuberculosis and from AIDS patients with disseminated pulmonary tuberculosis. Apoptosis was increased three-fold in BAL cells obtained from patients with pulmonary tuberculosis and even more markedly in alveolar macrophages of MTB-infected AIDS patients, compared with controls. Apoptosis was analysed and characterized by propidium iodide (PI) incorporation, terminal deoxy transferase (TDT)-mediated dUTP-biotin nick end labelling (TUNEL), and tissue transglutaminase (tTG) expression. The MTB–macrophage interaction was also investigated in vitro by infecting monocyte-derived macrophages (MDM) with MTB (virulent strain H37Rv). The induction of apoptosis by MTB required viable bacteria, was dose-dependent, and was restricted to H37Rv. Infection with either Mycobacterium avium complex (MAC) or HIV-1 and treatment with heat-killed MTB failed to induce apoptosis. © 1997 by John Wiley & Sons, Ltd.     

Blood Monocyte and Neutrophil Functions in the Acquired Immune Deficiency Syndrome

The acquired immune deficiency syndrome (AIDS) is characterized by infections with microorganisms against which phagocytes (especially monocytes/macrophages) play an important role. Therefore, various functions of blood monocytes and neutrophils were tested in 16 patients with AIDS. Neutrophil chemotactic responses towards casein and N-formyl-methionyl-L-leucyl-L-phenylalanine were depressed in patients with a short duration of disease (n = 9), whereas they were normal in those with a longer duration (n = 5), P less than 0.05. Neutrophil superoxide anion release was normal. In contrast, we found no evidence of an altered monocyte activity in the patients, since chemotactic responsiveness, phagocytosis of opsonized Candida albicans, and superoxide anion release were all normal. These findings suggest that the depressed neutrophil chemotaxis may play an important role in the high incidence of opportunistic infections in AIDS. Furthermore, it appears that in AIDS the immune deficiency does not extend to peripheral blood monocytes, but it does not exclude the possibility that the function of tissue macrophages is abnormal.     

Bronchoalveolar Lavage Cells and Mitotic Activity of Monocytes and Macrophages in Rats after Long-Term Intermittent Hypoxia

Long-term (1.5 months) intermittent hypoxia promoted desquamation of bronchial epithelial cells, decreased the relative content of alveolar macrophages and monocytes in bronchoalveolar lavage, stimulated lymphocyte migration to the lungs, and increased the relative content of lymphoid cell in rats. Mitotic activity of monocytes and macrophages decreased against the background of intraalveolar lymphocytosis (lymphocytic alveolitis).     

Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats

New evidence indicates that neural mechanisms can down-regulate acute inflammation. In these studies, we tested the potential role of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in a rodent model of acid-induced acute lung injury. We first determined that the alpha7 nAChR was expressed by alveolar macrophages and lung epithelial cells. Then, using an acid-induced acute lung injury mouse model, we found that nicotine, choline, and PNU-282,987 (a specific alpha7 nAChR agonist) decreased excess lung water and lung vascular permeability, and reduced protein concentration in the bronchoalveolar lavage (BAL). Deficiency of alpha7 nAChR resulted in a 2-fold increase in excess lung water and lung vascular permeability. The reduction of proinflammatory cytokines (macrophage inflammatory protein-2 and TNF-alpha) in the BAL with nicotine probably resulted from the suppression of NF-kappaB activation in alveolar macrophages. The beneficial effect of nicotine was also tested in rat model of acid-induced acute lung injury in which BAL protein and receptor for advanced glycation end products (RAGE), a marker of type I cell injury, were reduced by nicotine treatment. These results indicate that activation of alpha7 nAChR may provide a new therapeutic pathway for the treatment of acute lung injury.