Bronchoalveolar Lavage Interleukin Research Articles

A study of IL-6, IL-8, and TNF-α as inflammatory markers in COPD patients

To assess the diagnostic value of interleukin 6 (IL-6), IL-8 and tumor necrosis factor-α (TNF-α) as inflammatory markers in chronic obstructive pulmonary disease (COPD) patients. IL-6, IL-8 and TNF-α levels were measured by ELISA in the serum and the bronchoalveolar lavage (BAL) in 10 control participants and 25 mild and moderate COPD patients, whereas 25 patients with severe COPD were studied for the serum level of these inflammatory biomarkers. The mean value and SD of BAL and serum IL-6, IL-8 and TNF-α levels were significantly higher in COPD patients when compared with control participants; the serum level of these biomarkers were also significantly higher in severe compared with mild and moderate COPD patients. Increased srum and/or BAL IL-6, IL-8 and TNF-α can be used as biomarkers of the systemic inflammatory response in COPD patients, and their levels are correlated with the severity of COPD. Egypt J Broncho 2014 8:91–99

1789 Bronchoalveolar Interleukin-1 Beta: A Marker of Bacterial Burden in Long Term Mechanical Ventilation Newborn with Ventilator-Associated Pneumonia

ObjectiveTo assess the relationship between concentrations of bronchoalveolar cytokines and bacterial burden (quantitative bacterial count) in long term mechanical ventilation newborn with a presumptive diagnosis of ventilator-associated pneumonia.InterventionsAccording to the...

Ozone Exposure Suppresses Proliferative Response in Mice Skin

Ozone Exposure Suppresses Proliferative Response in Mice Skin

Sepsis by using Cecal Ligation and Single Puncture Causes Alveolar Space Enlargement in LPA2 Knockout Mice

Lysophosphatidic acid (LPA) plays a dual-function in lung inflammatory diseases. LPA receptors contribute to the pathogenesis of asthma, acute lung injury, and fibrosis. Here, we investigate the role of LPA receptor type 2 (LPA2) in sepsis-induced lung inflammation and injury. Sepsis was induced using cecal ligation and single puncture (CLP) with 27 gauge needle. Plasma interleukin-6 (IL-6) and KC levels were elevated in septic wild type and LPA2-/- mice, while septic LPA2-/- mice reduces plasma KC, not IL-6 levels, compared to septic wild type mice. Bronchoalveolar lavage (BAL) KC levels increased in septic wild type and LPA2-/- mice, while the sepsis had no effect on BAL IL-6 levels, protein leak, and inflammatory cell infiltration in the lungs in wild type and LPA2-/- mice. Hematoxylin and eosin (H&E) staining revealed that septic LPA2-/- mice aggravated alveolar space enlargement. Western blotting analysis of lung tissues demonstrate that the level of cortactin, an F-actin binding protein, was decreased in septic LPA2-/- mice, when compared to wild type mice. The level of immunoglobulin G (IgG) in BAL fluids significantly increased in septic LPA2-/- mice, when compared to septic wild type mice and sham mice. Furthermore, we found that sham and septic LPA2-/- mice increased surfactant proteins B, C, and D (SP-B, SP-C, and SP-D) expression in lungs, while SP-A levels in lungs was decreased in sham and septic LPA2-/- mice. These results suggest LPA2 may regulate cortactin and surfactant protein expression in the lung. LPA2 and its downstream signaling may play a protective role against sepsis induced emphysema like disease.

Bronchoalveolar Interleukin-1 Beta: A Marker of Bacterial Burden in Critcally Ill Children with Nosocomial Pneumonia

Objective: To assess the relationship between concentrations of bronchoalveolar cytokines and bacterial burden in critically ill children with a presumptive diagnosis of nosocomial pneumonia.Patients: According to the time course of nosocomial pneumonia at the time of study with bronchoalveolar lavage, 62 critically ill children with nosocomial pneumoniaInterventions: According to the time course of ventilator-associated pneumonia at the time of study with bronchoalveolar lavage, 62 children were divided into two subgroups: referral (n=32), and treated (n=30) nosocomial pneumonia. Bronchoalveolar lavage was performed in the most abnormal area on chest radiograph by fiberoptic bronchoscope. The concentrations of bronchoalveolar lavage cytokines.Measurement and main Results: 34 patients had a positive bacterial culture (bronchoalveolar lavage > or = 10 colony-forming units/mL), and made up 82% of pathogens recovered at high concentrations. The concentrations of bronchoalveolar lavage interleukin-1 beta were 204.2 +/− 15.7 and 38.2 +/− 12.6 pg/mL (mean +/− se) in the children with positive and negative bacterial culture, respectively (p < .001). Bronchoalveolar lavage interleukin- 1 beta was significantly higher in the children with a high bacterial burden (p < 0.001), with mixed bacterial infection (p < 0.001), and with nosocomial pneumonia (p < 0.001), compared with values in patients without these features.Conclusions: Since the concentration of bronchoalveolar lavage interleukin-1 beta was correlated with bacterial burden in the alveoli, it may be a marker for progressive and ongoing inflammation in critically ill children.

S50 Evaluation of secretory leucoprotease inhibitor (SLPI) as an anti-inflammatory therapy for donor lung inflammation

IntroductionDonor lung inflammation, reflected by high concentrations of interleukin-8 in bronchoalveolar lavage (BAL) and an imbalance between pro-inflammatory IL-6 and anti inflammatory IL-10 in tissue, correlates with poor graft function...

Stability of interleukin 8 and neutrophil elastase in bronchoalveolar lavage fluid following long-term storage

Background Interleukin-8 (IL-8) and neutrophil elastase (NE) are commonly measured markers of inflammation in bronchoalveolar lavage (BAL) fluid from patients with cystic fibrosis. Longitudinal analysis assumes uniform stability during storage, however the effect of extended low-temperature storage on these markers remains unclear. Methods BAL fluid from 104 children with cystic fibrosis was assayed for IL-8 and NE after storage at 4 °C for 7 days and − 80 °C for up to 6 years and compared with the initial assays performed soon after collection. Results IL-8 levels were stable after any measured length of time at − 80 °C or 4 °C. NE levels were stable for 6 months at − 80 °C but decreased beyond that or after 7 days at 4 °C. Conclusions Our data support the stability of IL-8 in BAL stored at − 80 °C for prolonged periods. NE in BAL decreases with storage and should be assayed as soon as practical after collection.

Plasma C-Reactive Protein Levels Correlate With Markers of Airway Inflammation After Lung Transplantation: A Role for Systemic Inflammation in Bronchiolitis Obliterans Syndrome?

Objective Plasma C-reactive protein (CRP) concentration has been associated with allograft dysfunction in cardiac and renal transplantation; data in lung transplantation (LTx), however, are lacking. We hypothesized that in Ltx, systemic inflammation may be associated with airway inflammation, which has an important role in the development of chronic allograft dysfunction or bronchiolitis obliterans syndrome after LTx. Methods In this retrospective, longitudinal, cohort study, plasma CRP concentration, bronchoalveolar lavage (BAL) inflammatory markers (interleukin [IL]–6 and IL-8 protein levels and cell differentials), and pulmonary function (forced expiratory volume in 1 second) were evaluated in 100 LTx recipients at discharge and at 3-, 6-, and 12-month follow-up. The Spearman rank test was used to determine a possible relationship between these parameters at each routine follow-up visit. Results Plasma CRP concentration positively correlated with BAL total cell count and neutrophilia, whereas there was a negative correlation with pulmonary function at discharge and at 3 and 6 months after LTx. A correlation between plasma CRP concentration and BAL interleukin levels was present at discharge (IL-6 and IL-8) and at 6 months (IL-8) after LTx. Conclusion Systemic inflammation and IL-8–mediated neutrophilic airway inflammation seem to be associated after LTx. Therefore, systemic inflammation has a possible role in the development of bronchiolitis obliterans syndrome after LTx.

Physiological noise versus white noise to drive a variable ventilator in a porcine model of lung injury

Variable ventilation is superior to control mode ventilation in a number of circumstances. The nature of the breathing file used to deliver the variable rate and tidal volume has not been formally examined. We compared two different noise files in a randomized prospective trial of variable ventilation. Pigs were anesthetized, intubated, and mechanically ventilated. Oleic acid was infused to introduce lung injury. The animals were ventilated at a tidal volume of 7 mL x kg(-1), in variable mode, with either physiologically-derived noise (variability file - 1,587 breath intervals-obtained from a spontaneously breathing volunteer; n = 10) or a variability file of identical length derived from computer- generated white noise (n = 10). The physiologically-derived noise had a power law alpha-exponent of -0.27 and a Hölder exponent of -0.38, indicative of auto-correlated noise. The computer-generated noise had an alpha-exponent of -0.52 and a Hölder exponent of -0.49, indicative of white noise. Both files showed multifractal characteristics. There were no differences between groups, at any time period, for PaO2, PaCO2, and static or dynamic respiratory system compliance. No differences were observed between groups for wet:dry lung weight ratios or for interleukin-8 in bronchoalveolar lavage fluid. This study demonstrates that the nature of the variability files, chosen to drive the variable ventilator, had no effect on indices of gas exchange or respiratory mechanics in this model. A considerable overlap of the multifractal files existed. The potential to drive a variable ventilator using algorithm-derived files with multifractal characteristics, thereby eliminating the requirement to use physiologically-derived signals, is discussed.

Airway Colonization and Gastric Aspiration After Lung Transplantation: Do Birds of a Feather Flock Together?

Both gastroesophageal reflux and airway colonization with Pseudomonas aeruginosa (P aeruginosa) are common in lung transplantation (LTx) recipients. There is mounting evidence that, due to their interaction with the epithelium, both may be involved in chronic allograft dysfunction/bronchiolitis obliterans syndrome (BOS) after LTx. We investigated whether gastric aspiration and airway colonization with P aeruginosa after LTx are associated. In this retrospective, cross-sectional, case-control study, 24 stable double (SS) LTx recipients were included. Markers of gastroesophageal reflux (pepsin, bile acids) and airway inflammation (neutrophilia and interleukin-8 (IL-8)) were evaluated in bronchoalveolar lavage (BAL) samples of post-operatively colonized (n = 12) and non-colonized matched-control LTx recipients (n = 12). BAL bile acid levels, but not pepsin levels, as well as neutrophilia and IL-8 protein levels were significantly elevated in colonized compared with non-colonized patients. Furthermore, bile acid levels, but not pepsin levels, correlated positively with BAL neutrophilia and IL-8 protein levels. Bile acid aspiration and airway colonization by P aeruginosa after LTx seem to be associated. This relationship between reflux and airway colonization and their role in the development of chronic allograft dysfunction/BOS after LTx should be further elucidated; nevertheless, induction of IL-8-mediated neutrophilic airway inflammation may be a putative mechanism.

Impact of Topical Cooling Solution and Prediction of Pulmonary Graft Viability From Non–heart-beating Donors

Functional assessment of the potentially damaged graft from a non-heart-beating donor (NHBD) is mandatory for successful outcome after transplantation. We investigated the impact of the topical cooling solution on graft preservation and whether inflammatory markers in bronchoalveolar lavage (BAL) can predict pulmonary graft viability in a pig ex vivo lung perfusion model. Pigs were euthanized and left untouched for 1 (SAL-1, PER-1) or 3 (SAL-3, PER-3) hours. Topical cooling was done with saline or low-potassium dextran solution (Perfadex) for 1 or 3 hours. In the heart-beating donor control group, the lungs were flushed, explanted and stored for 4 hours. BAL samples were taken from right lungs after explantation and assessed for nitrite, interleukin-8 (IL-8) and protein levels. Left lungs were prepared for ex vivo evaluation. Hemodynamic and oxygenation parameters were measured. Pulmonary vascular resistance (PVR), oxygenation index and Pao(2)/Fio(2) ratio differed significantly between the SAL-3 (42.2 +/- 6.0, 15.9 +/- 3.2 and 148 +/- 14.6 Wood units, respectively) and PER-3 (23.9 +/- 2.7, 6.4 +/- 0.8 and 221.7 +/- 15.06 Wood units, respectively) groups (p < 0.05). BAL IL-8 levels were higher in the SAL-3 group compared with the PER-3 group. BAL nitrite and protein levels were statistically higher in the SAL-3 group (0.98 +/- 0.17 micromol/liter, 728.3 +/- 75.7 microg/ml) than in the PER-3 (0.22 +/- 0.09 micromol/liter, 393.3 +/- 51.1 microg/ml) group (p < 0.05) and correlated with an increase in PVR (r = 0.623, p = 0.001; r = 0.530, p = 0.006, respectively). After 3 hours of warm ischemia topical cooling with Perfadex resulted in better graft function. Nitrite and protein levels in BAL correlated well with PVR and may therefore be used as a non-invasive marker to predict graft function for NHBDs.

Effects of Gasoline Engine Emissions on Preexisting Allergic Airway Responses in Mice

Gasoline-powered vehicle emissions contribute significantly to ambient air pollution. We hypothesized that exposure to gasoline engine emissions (GEE) may exacerbate preexisting allergic airway responses. Male BALB/c mice were sensitized by injection with ovalbumin (OVA) and then received a 10-min aerosolized OVA challenge. Parallel groups were sham-sensitized with saline. Mice were exposed 6 h/day to air (control, C) or GEE containing particulate matter (PM) at low (L), medium (M), or high (H) concentrations, or to the H level with PM removed by filtration (high-filtered, HF). Immediately after GEE exposure mice received another 10-min aerosol OVA challenge (pre-OVA protocol). In a second (post-OVA) protocol, mice were similarly sensitized but only challenged to OVA before air or GEE exposure. Measurements of airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL), and blood collection were performed ∼24 h after the last exposure. In both protocols, M, H, and HF GEE exposure significantly decreased BAL neutrophils from nonsensitized mice but had no significant effect on BAL cells from OVA-sensitized mice. In the pre-OVA protocol, GEE exposure increased OVA-specific IgG1 but had no effect on BAL interleukin (IL)-2, IL-4, IL-13, or interferon (IFN)-γ in OVA-sensitized mice. Nonsensitized GEE-exposed mice had increased OVA-specific IgG2a, IgE, and IL-2, but decreased total IgE. In the post-OVA protocol, GEE exposure reduced BAL IL-4, IL-5, and IFN-γ in nonsensitized mice but had no effect on sensitized mice. These results suggest acute exposure to the gas–vapor phase of GEE suppressed inflammatory cells and cytokines from nonsensitized mice but did not substantially exacerbate allergic responses.

Effects of Hardwood Smoke Exposure on Allergic Airway Inflammation in Mice

Hardwood smoke (HWS) from wood burning stoves and fireplaces can be a significant contributor to the composition of ambient air pollution. We hypothesize that the inhalation of HWS by ovalbumin (OVA)-sensitized mice with preexisting lung inflammation leads to the exacerbation of allergic airway responses. Two different models were employed to characterize the effects of inhaled wood smoke on allergic airway inflammation. In both models, male BALB/c mice were sensitized by injection with OVA and alum. In one model, mice were challenged by inhalation with OVA 1 day prior to exposure to HWS (30, 100, 300, or 1000 μg particulate matter [PM]/m3) for 6 h/day on 3 consecutive days. In the other model, mice were exposed by inhalation to OVA, rested for 11 days, were exposed to HWS for 3 consecutive days, and then were exposed to OVA immediately after the final HWS exposure. Bronchoalveolar lavage (BAL), and blood collection were performed ∼ 18 h after the last HWS or OVA exposure. HWS exposure after the final allergen challenge (first model) led to a significant increase in BAL eosinophils only at the 300 μg/m3 level. In contrast, changes in BAL cells did not reach statistical significance in the second model. There were no HWS-induced changes in BAL interleukin (IL)-2, IL-4, IL-13, and interferon (IFN)γ levels in either model following OVA challenge. These results suggest that acute HWS exposure can minimally exacerbate some indices of allergic airway inflammation when a final OVA challenge precedes HWS exposure, but does not alter Th1/Th2 cytokine levels.

The anti-inflammatory effect of inhaled nitric oxide on pulmonary inflammation in a swine model

Cardiopulmonary bypass (CPB) is associated with an inflammatory process that leads to lung injury. In this study, we hypothesized that inhaled nitric oxide (INO) possesses the ability to modulate CPB-induced inflammation. Fifteen male pigs were randomly divided into 3 groups: Sham, CPB+LPS (CPB and lipopolysaccharide), and CPB+LPS+INO. INO (20 parts per million) was administered for 24 h after anesthesia. CPB was performed for 90 min, and LPS was infused (1 microg/kg) after CPB. Bronchoalveolar lavage (BAL) fluid and blood were collected at T0 (before CPB), at 4 h, and at 24 h. At 24 h, BAL interleukin-8 (IL-8) levels were not increased as expected in the CPB+LPS group compared with the Sham group, but they were reduced significantly in the CPB+LPS+INO group. Cell hypo reactivity observed in the groups receiving LPS also seemed to downregulate endothelial nitric oxide synthase NOS protein expression relative to the Sham group. Nitrite and nitrate (NOx) concentrations were decreased significantly in the groups without INO. Moreover, animals treated with INO showed higher rates of pulmonary apoptosis compared with their respective controls. These results demonstrate that NOx production is reduced after CPB and that INO acts on the inflammatory process by diminishing neutrophils and their major chemoattractant, IL-8. INO also increases cell apoptosis in the lungs under inflammatory conditions, which may explain, in part, how it resolves pulmonary inflammation.

Pentoxifylline reduces acute lung injury in chronic endotoxemia

Background. Pentoxifylline (PTX) attenuates end-organ injury in models of sepsis and hemorrhage. PTX is thought to act by inhibiting phosphodiesterase, thus increasing cAMP and decreasing tumor necrosis factor-α (TNF-α) synthesis. The effects of PTX on neutrophil and endothelial cell adhesion molecules and, ultimately, organ injury in a chronic endotoxemia model have not been studied. We hypothesized that continuous infusion of PTX reduces acute lung injury (ALI) caused by chronic lipopolysaccharide (LPS) exposure. Materials and methods. Male Sprague-Dawley rats were given continuous infusion of LPS, PTX + LPS combined, or saline (sham) by implantable pumps. Neutrophil CD11b expression, lung histopathology, lung intercellular adhesion molecule-1 (ICAM-1) expression assessed by immune staining, serum TNF-α, serum interleukin-6 (IL-6), and bronchoalveolar lavage (BAL) IL-8 were evaluated at different time points. Lung injury was graded in a blinded fashion from 0 (normal) to 4 (severe) for interstitial inflammation, neutrophil infiltration, congestion, and edema. Total lung injury score (TLIS) was calculated by adding listed categories. White cell count in the peripheral blood and in the BAL was also performed. Results. Animals treated with PTX + LPS showed a significant reduction in lung injury score, a marked decrease in ICAM-1 expression, and a significant decrease in IL-8 levels in the BAL and serum IL-6 levels when compared with LPS-treated animals. Conclusions. Continuous infusion of PTX reduces ALI caused by chronic endotoxemia. The effect seems to be a result of decreased expression of endothelial and epithelial ICAM-1 and modulation of proinflammatory cytokine synthesis.

Bronchoalveolar interleukin-1 beta: a marker of bacterial burden in mechanically ventilated patients with community-acquired pneumonia.

To assess the relationship between concentrations of bronchoalveolar cytokines and bacterial burden (quantitative bacterial count) in intubated patients with a presumptive diagnosis of community-acquired pneumonia. A cross-sectional and clinical investigation. SETTING Medical/surgical and respiratory intensive care unit of a tertiary 1,200-bed medical center. According to the time course of community-acquired pneumonia at the time of study with bronchoalveolar lavage, 69 mechanically ventilated patients were divided into three subgroups: primary (n = 11), referral (n = 23), and treated (n = 35) community-acquired pneumonia. Bronchoalveolar lavage was performed in the most abnormal area on chest radiograph by fiberoptic bronchoscope. Bronchoalveolar lavage fluid was processed for quantitative bacterial culture. The concentrations of bronchoalveolar lavage cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, interleukin-8, and interleukin-10) also were measured. Thirty-two patients had a positive bacterial culture (bronchoalveolar lavage > or = 10 colony-forming units/mL)., and made up 76% of pathogens recovered at high concentrations. The concentrations of bronchoalveolar lavage interleukin-1 beta were 199.1 +/- 32.1 and 54.9 +/- 13.0 pg/mL (mean +/- se) in the patients with positive and negative bacterial culture, respectively (p < .001). Bronchoalveolar lavage interleukin- 1 beta was significantly higher in the patients with a high bacterial burden (p < .001), with mixed bacterial infection (p < .001), and with pneumonia (p < .001), compared with values in patients without these features. The relationship between bacterial load and concentrations of bronchoalveolar lavage interleukin-1 beta was very strong in the patients with primary and referral community-acquired pneumonia but was borderline in treated community-acquired pneumonia. The common pathogens were similar to the core pathogens of hospital-acquired pneumonia, probably due to antibiotic effects, delayed sampling, and superimposed nosocomial infection. Since the concentration of bronchoalveolar lavage interleukin-1 beta was correlated with bacterial burden in the alveoli, it may be a marker for progressive and ongoing inflammation in patients who have not responded to pneumonia therapy and who have persistence of bacteria in the lung.

Shock-Induced Neutrophil Mediated Priming for Acute Lung Injury in Mice: Divergent Effects of TLR-4 and TLR-4/FasL Deficiency

Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock/trauma, however, modeling this process in mice with a single shock or septic event is inconsistent. One explanation is that hemorrhage is often just a "priming insult," thus, secondary stimuli may be required to "trigger" ALI. To test this we carried out studies in which we assessed the capacity of hemorrhage alone or hemorrhage followed by septic challenge (CLP) to induce ALI. Lung edema, bronchoalveolar lavage interleukin (IL)-6, alveolar congestion, as well as lung IL-6, macrophage inflammatory protein (MIP)-2, and myeloperoxidase (MPO) activity were all increased in mice subjected to CLP at 24 but not 72 hours following hemorrhage. This was associated with a marked increase in the susceptibility of these mice to septic mortality. Peripheral blood neutrophils derived from 24 hours post-hemorrhage, but not Sham animals, exhibited an ex vivo decrease in apoptotic frequency and an increase in respiratory burst capacity, consistent with in vivo "priming." Subsequently, we observed that adoptive transfer of neutrophils from hemorrhaged but not sham-hemorrhage animals to neutropenic recipients reproduce ALI when subsequently septically challenged, implying that this priming was mediated by neutrophils. We also found marked general increases in lung IL-6, MIP-2, and MPO in mice deficient for toll-like receptor (TLR-4) or the combined lack of TLR-4/FasL. However, the TLR-4 defect markedly attenuated neutrophil influx into the lung while not altering the change in local cytokine/chemokine expression. Alternatively, the combined loss of FasL and TLR-4 did not inhibit the increase in MPO and exacerbated lung IL-6/MIP-2 levels even further.

Upregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration

Background: The early stage of post-transplant obliterative bronchiolitis (OB) is characterized by an influx of inflammatory cells to the lung, among which neutrophils may play a role in key events. The potential for chemokines to induce leukocyte accumulation in the alveolar space was investigated. We assessed whether changes in the chemotactic expression profile could be used as sensitive markers of the onset of OB. Methods: Serial bronchoalveolar lavage (BAL) fluids from 13 stable healthy recipients and 8 patients who developed bronchiolitis obliterans syndrome (BOS) were analyzed longitudinally for concentrations of interleukin-8 (IL-8), chemokines regulated-upon-activation and normal T-cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). These were assessed by enzyme-linked immunosorbent assay (ELISA). Results: Significantly elevated percentages of BAL neutrophils and IL-8 levels were found at the pre-clinical stage of BOS, on average 151 ± 164 days and 307 ± 266 days, respectively, before diagnosis of BOS. There was also early upregulation of RANTES and MCP-1 in the BOS group (mean 253 ± 323 and 152 ± 80 days, respectively, before diagnosis of BOS). The level of MCP-1 was consistently higher than that of RANTES until airway obliteration. BAL sICAM-1 and sVCAM-1 levels were not statistically different between the groups. Conclusions: These data support the belief that RANTES, IL-8 and MCP-1 play a crucial role in the pathogenesis of OB. The results show that relevant increased levels of such chemokines may predict BOS, and suggest that there is potential for some of these markers to be used as early and sensitive markers of the onset of BOS. Longitudinal monitoring of these chemokine signals may contribute to better management of patients at risk for developing OB, at a stage when remodeling can either be reversed or altered.

The selective phosphodiesterase 4 inhibitor RP 73-401 reduced matrix metalloproteinase 9 activity and transforming growth factor-beta release during acute lung injury in mice: the role of the balance between Tumor necrosis factor-alpha and interleukin-10.

Matrix metalloproteinases (MMPs) and transforming growth factor (TGF)-beta are involved in airway remodeling associated with the inflammatory process. In this study, we investigated the effect of RP 73-401 (piclamilast), a selective phosphodiesterase-4 inhibitor, on MMP-9 activity and TGF-beta production in two murine models of acute inflammation. In the first model, the lipopolysaccharide (LPS)-induced increase in neutrophils, MMP-9 activity, and tumor necrosis factor (TNF)-alpha and TGF-beta release in bronchoalveolar lavage (BAL) was significantly reduced by RP 73-401 pretreatment. In contrast, the BAL interleukin (IL)-10 level was decreased by LPS but restored by RP 73-401. IL-10 administration in LPS-exposed mice elicited a significant reduction in BAL neutrophilia, MMP-9 activity, and TNF-alpha release but not in TGF-beta production. In the second model, RP 73-401 inhibited BAL neutrophils but not MMP-9 activity and TGF-beta production that were induced by intranasal TNF-alpha. We demonstrated that RP 73-401 might modulate the expression of airway remodeling-associated mediators such as MMP-9 and TGF-beta and that this effect seemed to be at least partially mediated by the balance between TNF-alpha and IL-10.

Neutrophil-associated activation markers in healthy smokers relates to a fall in DLCOand to emphysematous changes on high resolution CT

Smoking is a risk factor for developing chronic obstructive pulmonary disease (COPD), but there are no good indicators for early identification of subjects who will develop symptomatic COPD. The aim of this study was to investigate inflammatory mechanisms related to changes in lung function and emphysematous changes on high resolution computed tomography (HRCT) in ‘healthy’ smokers. Subjects were 60-year-old men from a population study. Bronchoscopy was performed in 30 smokers and 18 who had never smoked. Blood tests, lung function measurements and HRCT were carried out in 58 and 34 subjects, respectively.In comparison with never-smokers, smokers had higher levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and lysozyme in blood, higher levels of MPO, interleukin-8 (IL-8) and HNL in bronchial lavage (BL), and of IL-8, HNL and interleukin-1 β (IL-1 β) in bronchoalveolar lavage (BAL). Smokers also had lower levels of Clara cell protein 16 (CC-16) in blood. HNL in BL and BAL showed strong correlations to other inflammatory markers (MPO, IL-8, IL-1 β). The variations in MPO in BL were explained by variations in HNL (R2=0·69), while these variations in BAL were explained by variations in HNL and IL-1β (R2=0·76). DLCOwas the lung function variable most closely related to MPO and IL-8 in BL and BAL and to IL-1 β in BAL. In a multiple regression analysis, MPO, IL-1 β, IL-8 and CC-16 in BL and MPO in BAL contributed to the explanation of variations in DLCOto 41% and 22%, respectively, independent of smoking habits. In smokers with emphysematous lesions on HRCT, HNL in BAL correlated to emphysema score (rs=0·71).We conclude that ‘healthy’ smoking men with a near normal FEV1show signs of inflammation in the lower airways that are related to a decrease in DLCOand to emphysematous lesions on HRCT. This inflammation seems to be the result of both monocyte/macrophage and neutrophil activation.