Phagocytic Activity Of Alveolar Macrophages Research Articles

Myeloid-derived suppressor cells impair alveolar macrophages through PD-1 receptor ligation during Pneumocystis pneumonia.

Myeloid-derived suppressor cells (MDSCs) were recently found to accumulate in the lungs during Pneumocystis pneumonia (PcP). Adoptive transfer of these cells caused lung damage in recipient mice, suggesting that MDSC accumulation is a mechanism of pathogenesis in PcP. In this study, the phagocytic activity of alveolar macrophages (AMs) was found to decrease by 40% when they were incubated with MDSCs from Pneumocystis-infected mice compared to those incubated with Gr-1(+) cells from the bone marrow of uninfected mice. The expression of the PU.1 gene in AMs incubated with MDSCs also was decreased. This PU.1 downregulation was due mainly to decreased histone 3 acetylation and increased DNA methylation caused by MDSCs. MDSCs were found to express high levels of PD-L1, and alveolar macrophages (AMs) were found to express high levels of PD-1 during PcP. Furthermore, PD-1 expression in AMs from uninfected mice was increased by 18-fold when they were incubated with MDSCs compared to those incubated with Gr-1(+) cells from the bone marrow of uninfected mice. The adverse effects of MDSCs on AMs were diminished when the MDSCs were pretreated with anti-PD-L1 antibody, suggesting that MDSCs disable AMs through PD-1/PD-L1 ligation during PcP.

Dead bacteria reverse antibiotic-induced host defense impairment in burns.

Burn patients can incur high rates of hospital-acquired infections. The mechanism of antibiotic exposure on inducing infection vulnerability has not been determined. This study aimed to examine the effects of antibiotic treatment on host defense mechanisms. First we treated C57/BL6 mice with combined antibiotic treatment after 30% to 35% total body surface area burn. Animals were sacrificed at 48 hours after sham or thermal injury treatment. Bacterial counts in intestinal lumen and mucosa were measured. Next, we treated animals with or without oral dead Escherichia coli or Staphylococcus aureus supplementation to stimulate Toll-like receptor in the intestinal mucosa. Toll-like receptor 4, antibacterial protein expression, nuclear factor (NF)-κB DNA-binding activity, and bacteria-killing activity in the intestinal mucosa; intestinal permeability; bacterial translocation to mesenteric lymph nodes; Klebsiella pneumoniae translocation; interleukin-6 in the blood; and phagocytic activity of alveolar macrophages, were assessed. Thermal injury increased microflora and NF-κB DNA-binding activity of the intestine. Systemic antibiotic treatment decreased gut microflora and increased bacterial translocation to mesenteric lymph nodes, intestinal permeability, and interleukin-6 levels in the blood. Antibiotic treatment also decreased bacteria-killing activity in intestinal mucosa and phagocytic activity of alveolar macrophages. Oral dead E coli and S aureus supplementation induced NF-κB DNA-binding activity, Toll-like receptor 4, and antibacterial protein expression of the intestinal mucosa. Taken together with the fact that dead bacteria reversed antibiotic-induced K pneumoniae translocation and intestinal and pulmonary defense impairment, we conclude that combined antibiotic treatment results in systemic host defense impairment in burns through the decrease in intestinal flora. We suggest that dead bacteria supplementation could induce nondefensin protein expression and reverse antibiotic-induced gut and lung defense impairment in burn patients.

Estrogen-mediated impairment of macrophageal uptake of environmental TiO2 particles to explain inflammatory effect of TiO2 on airways during pregnancy

Innate defenses against environmental particulate exposures can become deficient when physiological background of the organism is unbalanced. Even those exposures considered innocuous may then become harmful. For example, one of the important inherent risks of pregnancy is increased inflammatory responsiveness in the airways, which extends to exposures considered otherwise innocuous: it has been observed that normally “inert” particulates become inflammatory in pregnancy. They lead to enhanced airway inflammation associated with increased asthma risk in the offspring in the BALB/c model. It was hypothesized that pregnancy hormones alter macrophageal uptake and clearance of particles. This study shows that the phagocytic activity of alveolar macrophages (AM) and RAW264.7 cells against titanium dioxide (TiO2) was inhibited in pregnancy by ∼10% and in vitro by estradiol by ∼20%; progesterone potentiated this effect. Hence, enhanced inflammation in pregnancy as an outcome of exposure to the “inert” TiO2 may be due to an effect of pregnancy hormones which decrease the ability of the airways to clear the particles. AM (at 106 cells/recipient) isogenically transplanted from pregnant mothers into airways of recipients were able to confer the phenotype of inflammatory response to TiO2 (PMN counts of 1.62 [± 0.19] × 105/ml versus 0.61 [± 0.13] × 105/ml in control). Because this small amount of transferred AM could not replace the AM population in the recipients’ lungs, it is postulated that the effect is mediated by inhibitory signaling factors that AM produce and release; hence, a list of probable molecules was identified via genome-wide microarray.

Effect of TiO<sub>2</sub> Nanofibres on Selected Bronchoalveolar Parameters in Acute and Subacute Phase - Experimental Study

Titanium dioxide nanofibres (TiO2) were intratracheally instilled in dose of 4 mg/0.2 mL saline solution per animal (Wistar rats). After 48 hours and 14 days the animals were exsanguinated (under i.p. thiopental narcosis), bronchoalveolar lavage (BAL) was perfomed and cells from BAL fluid were isolated. Following inflammatory, cytotoxic and oxidative stress BAL parameters were examined: differential cell count (% of alveolar macrophages (AM), polymorphonuclears and lymphocytes); the viability and phagocytic activity of AM; the proportion of immature cells; the proportion of multinucleated cells; count of AM/mL lavage; count of BAL cells/mL lavage; the level of ascorbic acid and activity of superoxide dismutase, both in tissue homogenate and in bronchoalveolar lavage fluid. The majority of examined BAL parameters in the acute and subacute phase in our study suggest serious inflammatory and cytotoxic processes in lung after exposure to TiO2.

Protective effect of procysteine on Acinetobacter pneumonia in hyperoxic conditions

Ventilator-associated pneumonia (VAP) is an important cause of morbidity and mortality in critical care settings. Acinetobacter has become a leading cause of VAP. In particular, the appearance and spread of multidrug-resistant Acinetobacter is of great concern. In this study, we examined the effect of the antioxidant procysteine on Acinetobacter murine pneumonia in hyperoxic conditions in order to simulate VAP. Acinetobacter was administered intranasally to BALB/c mice kept in hyperoxic conditions. At designated timepoints, bacterial number, cytokine production and histopathological findings in the lungs were examined. The effects of procysteine on survival rates, lung bacterial burdens and the phagocytic activities of alveolar macrophages were evaluated. Drastic decreases in survival were observed when the infected mice were kept in hyperoxic conditions (P < 0.001). Significant differences in pulmonary bacterial number and neutrophil accumulation were observed between mice kept in hyperoxic or normoxic conditions on day 3. Although all mice infected with Acinetobacter spp. and kept in hyperoxic conditions died by day 3, procysteine treatment significantly improved survival (60% survival on day 7, P < 0.01). Procysteine treatment decreased the lung bacterial burden on days 2 and 3. Finally, improved uptake of FITC-labelled beads by alveolar macrophages from mice treated with procysteine and kept in hyperoxic conditions was noted. These results suggest that hyperoxia increases mortality in mice with Acinetobacter pneumonia and that procysteine improves survival by increasing the phagocytic activity of alveolar macrophages in mice kept in hyperoxic conditions.

TLR7 Contributes to the Rapid Progression but Not to the Overall Fatal Outcome of Secondary Pneumococcal Disease following Influenza A Virus Infection

Increased risk for bacterial superinfections substantially contributes to the mortality caused by influenza A virus (IAV) epidemics. While the mechanistic basis for this lethal synergism is still insufficiently understood, immune modulation through the viral infection has been shown to be involved. Since the pattern-recognition receptor (PRR) toll-like receptor 7 (TLR7) is a major sensor for the viral genome, we studied how IAV recognition by TLR7 influences the development of secondary pneumococcal infection. In a mouse model of IAV, TLR7-deficient hosts induced a potent antiviral response and showed unchanged survival. In secondary pneumococcal infection during acute influenza, TLR7ko mice showed a fatal outcome similar to wild-type (WT) hosts, despite significantly delayed disease progression. Also, when bacterial superinfection occurred after virus clearance, WT and TLR7-deficient hosts showed similar mortality, even though we found the phagocytic activity of alveolar macrophages isolated from IAV-pre-infected hosts to be enhanced in TLR7ko over WT mice. Thus, we show that a virus-sensing PRR modulates the progression of secondary pneumococcal infection following IAV. However, the fatal overall outcome in WT as well as TLR7ko hosts suggests that processes distinct from TLR7-triggering override the contribution of this single PRR.

SELECTIVE EFFECTS OF PULMONARY SURFACTANT ON VARIOUS SUBPOPULATIONS OF ALVEOLAR MACROPHAGES IN THE MODEL OF EXPERIMENTAL TUBERCULOSIS

Pulmonary surfactant is necessary component for maintenance of high level of phagocytic activity of alveolar macrophages. Tuberculosis inflammation reduces the production of surfactant by type II cells and phagocytic activity of alveolar macrophages. The effects of exogenous pulmonary surfactant on the ultrastructural changes of various subpopulations of alveolar macrophages were studied by TEM-method. For investigations the bronchial alveolar lavage fluid from guinea pigs infected of M. tuberculosis and treated by isoniatid or isoniazid + exogenous pulmonary surfactant were used. It was shown that isoniazid + exogenous pulmonary surfactant normalizes the heterogeneous population of alveolar macrophages providing stimulating effects on their maturation and phagocytic activity more effectively than isoniazid therapy.

Crotonaldehyde induces apoptosis and immunosuppression in alveolar macrophages

Crotonaldehyde, a highly toxic α, β-unsaturated aldehyde, is a major component of cigarette smoke (CS) and a ubiquitous environmental pollutant. Exposure to crotonaldehyde-rich pollutants such as CS is associated with suppression of respiratory host defense against infections. The aim of this study was to evaluate the apoptotic and immunological effects of crotonaldehyde exposure in a rat alveolar macrophage (AM) cell line, NR8383. Our studies showed that crotonaldehyde induced AM cell death mainly via the apoptotic process. Crotonaldehyde also decreased the phagocytic activity of AMs. Crotonaldehyde caused inhibition of NO, TNF-α, IL-1β and IL-12 production in AMs treated with lipopolysaccharide (LPS), which is probably related to inhibition of NF-κB activation. These results indicate that crotonaldehyde can cause adverse effects in AMs via multiple mechanisms, and may contribute to compromised lung immunological response in smokers.

Oxidized phospholipids impair pulmonary antibacterial defenses: Evidence in mice exposed to cigarette smoke

Patients with COPD are associated with poor pulmonary anti-bacterial innate defenses, which increase the risk for frequent acute exacerbations caused by bacterial infection. Despite elevated numbers of phagocytes (macrophages and neutrophils), airways of patients with COPD show stable bacterial colonization. A defect in the phagocytic ability of alveolar macrophages (AMs) is one of the primary reasons for failure to clear the invading bacteria in airways of smokers and COPD patients and also in mice exposed to cigarette smoke (CS). Oxidative stress, as a result of CS exposure is implicated; however, the factors or mediators that inhibit phagocytic activity of AMs in lungs of smokers remain unclear. In the current study, we provide evidence that accumulation of oxidized phospholipids (Ox-PLs) mediate inhibition of phagocytic function of AMs in CS-exposed mice. Mice exposed to 6months of CS showed impaired bacterial phagocytosis and clearance by AMs and elevated levels of Ox-PLs in bronchoalveolar lavage fluid (BALF), compared to mice exposed to room air. Intratracheal instillation of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OX-PAPC) inhibited phagocytic activity of AMs and impaired pulmonary bacterial clearance in mice. In vitro studies demonstrated that exposure of J774 macrophages to OX-PAPC inhibited bacterial phagocytosis and clearance. However, pre-treatment of OX-PAPC with the monoclonal antibody EO6, which specifically binds to oxidized phospholipid but not native phospholipid, abolished OX-PAPC induced inhibition of bacterial phagocytosis and clearance. Incubation of BALF retrieved from CS-exposed mice impaired bacterial phagocytosis by J774 macrophages, which was abolished by pre-treatment of BALF with the EO6 antibody. In conclusion, our study shows that Ox-PLs generated following chronic CS exposure could play a crucial role in inhibiting phagocytic function of AMs and thus impair pulmonary anti-bacterial innate defenses in CS-exposed mice. Therapeutic approaches that augment pulmonary antioxidant defenses could be beneficial in reducing oxidative stress-driven impairment of phagocytosis by AMs in smokers and COPD patients.

Expression and preliminary functional analysis of Siglec-F on mouse macrophages

Sialic acid-binding immunoglobulin-like lectin (Siglec)-F is a mouse functional paralog of human Siglec-8 that induces apoptosis in human eosinophils, and therefore may be useful as the basis of treatments for a variety of disorders associated with eosinophil hyperactivity, such as asthma. The expression pattern and functions of this protein in various cell types remain to be elucidated. The aim of this study was to determine the expression of Siglec-F on mouse macrophages by immunocytochemical staining, and also to investigate the effects of Siglec-F engagement by a Siglec-F antibody on phagocytic activity of macrophages. The results showed that Siglec-F expression was detected on mouse alveolar macrophages, but not on peritoneal macrophages. Furthermore, Siglec-F engagement did not affect the phagocytic activity of alveolar macrophages in the resting state or in the activated state following stimulation by the proinflammatory mediator tumor necrosis factor alpha (TNF-α) or lipopolysaccharide (LPS). Siglec-F expression on alveolar macrophages may be a result of adaptation. Macrophages actively regulate immune responses via production of cytokines. Therefore, further investigation of the effects of Siglec-F engagement on immune mediators or cytokines released by alveolar macrophages is required.

The Influence of Cigarette Smoke on the Selected Bronchoalveolar Cells in Experiment

The occurence of lung diseases (obstructive, malignant) resulting from smoking has an increasing tendency. The lung is the primary organ at risk from the effects of inhaled cigarette smoke and smoking has been implicated as a contributing factor to the causation of various respiratory diseases. The aim of presented work was to find out the subchronic effect of the 6-month exposure to cigarette smoke on the selected inflammatory and cytotoxic parameters of bronchoalveolar lavage in W rats and thus to contribute to understanding of the mechanism of action of tobacco smoke and/or path mechanism of lung injury developed after cigarette smoking. In special chamber, the animals smoked 8 standard research 1R1 type of cigarettes per day, except Saturdays and Sundays, during 6 months. The daily concentration of total particulate matter (TPM)/m3 air for two hours per exposure requiring to burn eight cigarettes was 85 mg. Animals were sacrificed after the 6-month exposure and bronchoalveolar lavage (BAL) was performed and selected inflammatory and cytotoxic BAL parameters were examined and compared with the control group. Following BAL parameters were investigated: the total cell and alveolar macrophages (AM) count in BAL, the differential cell count (% of AM, % of polymorphonuclears--PMN, % of lymphocytes--Ly), proportion of immature AM, proportion of bi-nucleated cells--BNC, viability, the phagocytic activity of AM, cytokines TNF-alpha (tumor necrosis factor alpha) and IL-1beta (interleukin-1beta). A) The 6-month smoking of eight cigarettes daily significantly changed prevailing number of examined BAL parameters; B) The presence of inflammatory and cytotoxic responses in lung tissue can probably signalize beginning or developing of disease process.

Phagostimulatory effect of uptake of PLGA microspheres loaded with rifampicin on alveolar macrophages

Our previous results on the phagocytic activity of alveolar macrophages (Mϕs) toward poly(lactic-co-glycolic) acid microspheres (PLGA MS) loaded with the anti-tuberculosis agent rifampicin (R-PLGA MS) suggest that the phagocytosis of R-PLGA MS enhances the phagocytic activity of Mϕ cells. To confirm this possibility, we examined the effect of phagocytosis of R-PLGA MS and polystyrene latex (PSL) MS on the phagocytic uptake of fluorescent PSL (F-PSL) MS by cells of the rat alveolar macrophage cell line NR8383 at 37°C. Phagocytic activity was examined in terms of the population of Mϕ cells that had phagocytosed MS (N(total)) and the total number of MS phagocytosed (n(total)) by counting the phagocytic Mϕ cells and the MS ingested in optical microscopic fields. Phagocytosis of R-PLGA MS enhanced about 1.5 times the values of N(total) and n(total) of the phagocytosis of F-PSL MS under the conditions where the phagocytosis of F-PSL MS did not attain the saturated level. In contrast, the phagocytosis of PSL MS did not enhance the phagocytic activity of Mϕ cells toward F-PSL MS. In conclusion, R-PLGA MS are favorable for drug delivery of anti-tuberculosis agents into alveolar Mϕs due to their ability to up-regulate the phagocytosis of MS.

Hydrogen peroxide enhances phagocytosis of Pseudomonas aeruginosa in hyperoxia

Mechanical ventilation with hyperoxia is a necessary treatment for patients with respiratory distress. However, patients on mechanical ventilation have increased susceptibility to infection. Studies including ours have shown that reactive oxygen species (ROS), generated by exposure to prolonged hyperoxia, can cause a decrease in the phagocytic activity of alveolar macrophages. Hydrogen peroxide (H2O2) is a form of ROS generated under hyperoxic conditions. In this study, we examined whether treatment with H2O2 directly affects macrophage phagocytic ability in RAW 264.7 cells that were exposed to either 21% O2 (room air) or 95% O2 (hyperoxia). Moderate concentrations (ranging from 10 to 250 µM) of H2O2 significantly enhanced macrophage phagocytic activity and restored hyperoxia-suppressed phagocytosis through attenuation of hyperoxia-induced disorganization of actin cytoskeleton and actin oxidation. These results indicate that H2O2 at low–moderate concentrations can be beneficial to host immune responses by improving macrophage phagocytic activity.

Microarray studies on effects of Pneumocystis carinii infection on global gene expression in alveolar macrophages

BackgroundPneumocystis pneumonia is a common opportunistic disease in AIDS patients. The alveolar macrophage is an important effector cell in the clearance of Pneumocystis organisms by phagocytosis. However, both the number and phagocytic activity of alveolar macrophages are decreased in Pneumocystis infected hosts. To understand how Pneumocystis inactivates alveolar macrophages, Affymetrix GeneChip® RG-U34A DNA microarrays were used to study the difference in global gene expression in alveolar macrophages from uninfected and Pneumocystis carinii-infected Sprague-Dawley rats.ResultsAnalyses of genes that were affected by Pneumocystis infection showed that many functions in the cells were affected. Antigen presentation, cell-mediated immune response, humoral immune response, and inflammatory response were most severely affected, followed by cellular movement, immune cell trafficking, immunological disease, cell-to-cell signaling and interaction, cell death, organ injury and abnormality, cell signaling, infectious disease, small molecular biochemistry, antimicrobial response, and free radical scavenging. Since rats must be immunosuppressed in order to develop Pneumocystis infection, alveolar macrophages from four rats of the same sex and age that were treated with dexamethasone for the entire eight weeks of the study period were also examined. With a filter of false-discovery rate less than 0.1 and fold change greater than 1.5, 200 genes were found to be up-regulated, and 144 genes were down-regulated by dexamethasone treatment. During Pneumocystis pneumonia, 115 genes were found to be up- and 137 were down-regulated with the same filtering criteria. The top ten genes up-regulated by Pneumocystis infection were Cxcl10, Spp1, S100A9, Rsad2, S100A8, Nos2, RT1-Bb, Lcn2, RT1-Db1, and Srgn with fold changes ranging between 12.33 and 5.34; and the top ten down-regulated ones were Lgals1, Psat1, Tbc1d23, Gsta1, Car5b, Xrcc5, Pdlim1, Alcam, Cidea, and Pkib with fold changes ranging between -4.24 and -2.25.ConclusionsIn order to survive in the host, Pneumocystis organisms change the expression profile of alveolar macrophages. Results of this study revealed that Pneumocystis infection affects many cellular functions leading to reduced number and activity of alveolar macrophages during Pneumocystis pneumonia.

Improvement in alveolar macrophage function after therapeutic lung lavage in pulmonary alveolar proteinosis

Alveolar macrophage (AM) function was investigated in 4 cases of pulmonary alveolar proteinosis (PAP). Therapeutic bronchoalveolar lavage (BAL) with a flexible bronchofiberscope was done 7-13 times during periods of 4-24 weeks. In the initial BAL, the total cell count was only 0.18-0.92 x 10(5)/ml. Also low AM, lymphocytosis and eosinophilia values were noted. The phagocytic activity of AM was only 3-14% and nitroblue tetrazonium (NBT) reduction of AM was under 5% before therapeutic BAL. However, the phagocytic activity was from 25-63% and NBT reduction from 15-35% after therapeutic BAL, AM function with periods of remission of PAP was normal but AM function decreased during relapse and exacerbation of PAP. After therapeutic BAL, two patients have been in remission for three years, one patient with incomplete restoration of AM function relapsed after one year, and one patient without restoration of AM function showed further deterioration after developing pulmonary tuberculosis. These findings indicate that the defect in AM function found in PAP is reversible with therapeutic BAL, and that the severity of PAP is closely associated with AM function.

Phagocytic Activity of Alveolar Macrophages in the Presence of Liposomal “Biene”

Phagocytic activity of alveolar macrophages isolated from rat bronchoalveolar lavage fluid was studied during their reaction with multilamellar liposomes containing biene (a complex of unsaturated fatty acids). Liposomes with incorporated biene significantly stimulated phagocytic activity of freshly isolated macrophages and primary culture of these cells (judging from the increase in phagocytic index and phagocytic number). A quantitative relationship between the phagocytic number and phagocytic index, on the one hand, and the concentration of liposomal biene, on the other, was detected. The effects of liposomes containing incorporated biene, liposomes of similar composition without biene, and pure biene substance on cell suspension were compared.

Commensal microflora induce host defense to E.coli pneumonia through toll-like receptors (133.13)

Abstract The role of commensal microflora in host response to pneumonia has not been defined. This study is to investigate whether commensal microflora in gut increase the host defense against pneumonia through TLRs signaling.We treated C3H/HeN and C3H/HeJ mice with antibiotics in drinking water for 4 weeks to deplete gut commensal microflora. At week 3, drinking water was supplemented with lipopolysaccharide (LPS); a ligand for TLR4, to trigger TLRs in intestinal tract. E.coli was injected to trachea to induce E.coli pneumonia. Commensal depletion induced a 15-fold and a 2.5-fold increase in E.coli pneumonia-induced bacterial counts in lung and blood, respectively and a 30% decrease of lung MPO activity. Commensal depletion induced a suppression of TLR4, TNFα&amp;, KC, and CXCR2 expression; and NF-κB activity in intestine and LPS supplement reversed them. LPS supplement increased lung MPO activity and decreased E.coli pneumonia-induced bacterial counts in WT mice but not in C3H/HeJ mice. Commensal depletion induced a decrease of phagocytic activity of alveolar macrophages, reduced NF-κB activity, and increased KC, MIP-2, and IL-1β mRNA expression of lung in WT mice but not in C3H/HeJ mice. In conclusions, commensal microflora are critical in inducing TLR4 expression and NF-κB activation of intestine, increasing the lung immunity, and decreasing the inflammatory signaling in lung after E.coli pneumonia. Given that the stimulatory effect of LPS supplement on lung immunity is abolished in TLR4-deficient mice, we conclude that both commensal microflora and TLR4 ligand increase host defense against pneumonia through toll-like receptors.

Perinatal environmental tobacco smoke exposure alters the immune response and airway innervation in infant primates

Epidemiologic studies associate environmental tobacco smoke (ETS) exposure with childhood asthma. To investigate whether specific pathophysiological alterations that contribute to asthma development in human beings can be induced in infant monkeys after perinatal ETS exposure. Rhesus macaque fetuses/infants were exposed to ETS at 1 mg/m(3) of total suspended particulate matter from 50 days gestational age to 2.5 months postnatal age. Inflammatory and neural responses to ETS exposure were measured in the infant monkeys. Perinatal ETS exposure could induce systemic and local responses, which include significant elevation of plasma levels of C5a and brain-derived neurotrophic factor, as well as significant increases in pulmonary expression of proinflammatory cytokine TNF-alpha and T(H)2 cytokine IL-5, chemokine monocyte chemoattractant protein 1, and the density of substance P-positive nerves along the bronchial epithelium. Perinatal ETS exposure also significantly increased the numbers of mast cells, eosinophils, monocytes, and lymphocytes in the lungs of infant monkeys. In addition, ex vivo measurements showed significantly increased levels of IL-4 and brain-derived neurotrophic factor in the culture supernatant of PBMCs. Interestingly, as an important component of cigarette smoke, LPS was detected in the plasma of infant monkeys subjected to perinatal exposure to ETS. In contrast, an inhibitory effect of perinatal ETS exposure was also observed, which is associated with decreased phagocytic activity of alveolar macrophages and a significantly decreased level of nerve growth factor in the bronchoalveolar lavage fluid. Perinatal ETS exposure can induce a T(H)2-biased inflammatory response and alter airway innervation in infant monkeys.

Macrophage Dysfunction and Susceptibility to Pulmonary Pseudomonas aeruginosa Infection in Surfactant Protein C-Deficient Mice

To determine the role of surfactant protein C (SP-C) in host defense, SP-C-deficient (Sftpc-/-) mice were infected with the pulmonary pathogen Pseudomonas aeruginosa by intratracheal injection. Survival of young, postnatal day 14 Sftpc-/- mice was decreased in comparison to Sftpc+/+ mice. The sensitivity to Pseudomonas bacteria was specific to the 129S6 strain of Sftpc-/- mice, a strain that spontaneously develops interstitial lung disease-like lung pathology with age. Pulmonary bacterial load and leukocyte infiltration were increased in the lungs of Sftpc-/- mice 24 h after infection. Early influx of polymorphonuclear leukocytes in the lungs of uninfected newborn Sftpc-/- mice relative to Sftpc+/+ mice indicate that the lack of SP-C promotes proinflammatory responses in the lung. Mucin expression, as indicated by Alcian blue staining, was increased in the airways of Sftpc-/- mice following infection. Phagocytic activity of alveolar macrophages from Sftpc-/- mice was reduced. The uptake of fluorescent beads in vitro and the number of bacteria phagocytosed by alveolar macrophages in vivo was decreased in the Sftpc-/- mice. Alveolar macrophages from Sftpc-/- mice expressed markers of alternative activation that are associated with diminished pathogen response and advancing pulmonary fibrosis. These findings implicate SP-C as a modifier of alveolar homeostasis. SP-C plays an important role in innate host defense of the lung, enhancing macrophage-mediated Pseudomonas phagocytosis, clearance and limiting pulmonary inflammatory responses.

Immunological Effect of PM 2.5 on Cytokine Production in Female Wistar Rats

To investigate the immunological effect of PM2.5 on cytokine production in female Wistar rats. Female Wistar rats were given 0.3 mg, 0.75 mg, 2 mg, 5 mg of PM2.5 per 0.5 mL saline, respectively. Saline was used as the negative control. TNF-alpha and IL-6 levels in the branchoalveolar lavage were measured by ELISA, and mRNA expression levels in lung tissue were detected by RT-PCR. Alveolar macrophages were collected for testing phogacytic function. Exposure to PM2.5 stimulated TNF-alpha production in a dose-dependent manner (P < 0.05), However, no statistically significant difference was found. No time-dependent change in TNF-a and IL-6 production was found. TNF-alpha and IL-6 mRNA expressions were induced by PM2.5-exposure. The phagocytic rate (PR) was significantly decreased by PM2.5 treatment. PM2.5 exposure increases inflammation response of the lung in a dose-dependent manner. Moreover, tissue injury induced by PM2.5 may be related to altered production of cytokines. PMz2.5 may impair the phagocytic activity of alveolar macrophages.