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Michael Minnicozzi - One of the best experts on this subject based on the ideXlab platform.
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comparison of pde 4 inhibitors rolipram and sb 207499 ariflotm in a rat model of pulmonary Neutrophilia
Pulmonary Pharmacology & Therapeutics, 2001Co-Authors: J Spond, Richard W Chapman, Jay S Fine, H Jones, William Kreutner, Ted T Kung, Michael MinnicozziAbstract:Abstract Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose–response experiments, we found that rats exposed to 10 μg or 100 μg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary Neutrophilia, provoked by the challenge of 10 μg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 μg LPS caused the local pulmonary production of TNF- α . In contrast to the cellular influx, TNF- α production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 β in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- α and IL-1 β was unaffected by either SB 207499 or rolipram. When provoked with the 10 μg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary Neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- α or the inhibition of IL-1 β , and occur independently of endogenous catecholamine or corticosteroid release.
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comparison of pde 4 inhibitors rolipram and sb 207499 ariflotm in a rat model of pulmonary Neutrophilia
Pulmonary Pharmacology & Therapeutics, 2001Co-Authors: J Spond, Richard W Chapman, Jay S Fine, H Jones, William Kreutner, Ted T Kung, Michael MinnicozziAbstract:Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose-response experiments, we found that rats exposed to 10 microg or 100 microg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary Neutrophilia, provoked by the challenge of 10 microg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 microg LPS caused the local pulmonary production of TNF- alpha. In contrast to the cellular influx, TNF- alpha production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 beta in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- alpha and IL-1 beta was unaffected by either SB 207499 or rolipram. When provoked with the 10 microg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary Neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- alpha or the inhibition of IL-1 beta, and occur independently of endogenous catecholamine or corticosteroid release.
J Spond - One of the best experts on this subject based on the ideXlab platform.
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comparison of pde 4 inhibitors rolipram and sb 207499 ariflotm in a rat model of pulmonary Neutrophilia
Pulmonary Pharmacology & Therapeutics, 2001Co-Authors: J Spond, Richard W Chapman, Jay S Fine, H Jones, William Kreutner, Ted T Kung, Michael MinnicozziAbstract:Abstract Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose–response experiments, we found that rats exposed to 10 μg or 100 μg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary Neutrophilia, provoked by the challenge of 10 μg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 μg LPS caused the local pulmonary production of TNF- α . In contrast to the cellular influx, TNF- α production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 β in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- α and IL-1 β was unaffected by either SB 207499 or rolipram. When provoked with the 10 μg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary Neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- α or the inhibition of IL-1 β , and occur independently of endogenous catecholamine or corticosteroid release.
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comparison of pde 4 inhibitors rolipram and sb 207499 ariflotm in a rat model of pulmonary Neutrophilia
Pulmonary Pharmacology & Therapeutics, 2001Co-Authors: J Spond, Richard W Chapman, Jay S Fine, H Jones, William Kreutner, Ted T Kung, Michael MinnicozziAbstract:Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose-response experiments, we found that rats exposed to 10 microg or 100 microg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary Neutrophilia, provoked by the challenge of 10 microg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 microg LPS caused the local pulmonary production of TNF- alpha. In contrast to the cellular influx, TNF- alpha production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 beta in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- alpha and IL-1 beta was unaffected by either SB 207499 or rolipram. When provoked with the 10 microg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary Neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- alpha or the inhibition of IL-1 beta, and occur independently of endogenous catecholamine or corticosteroid release.
Renaud Louis - One of the best experts on this subject based on the ideXlab platform.
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distribution of sputum cellular phenotype in a large asthma cohort predicting factors for eosinophilic vs neutrophilic inflammation
European Respiratory Journal, 2013Co-Authors: Florence Schleich, Monique Henket, Maïté Manise, Jocelyne Sele, Laurence Seidel, Renaud LouisAbstract:Background Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors of sputum inflammatory phenotypes according to easily available clinical characteristics. Methods This retrospective study was conducted in 508 asthmatics with successful sputum induction recruited from the University Asthma Clinic of Liege. Receiver-operating characteristic (ROC) curve and multiple logistic regression analysis were used to assess the relationship between sputum eosinophil or neutrophil count and a set of covariates. Equations predicting sputum eosinophils and neutrophils were then validated in an independent group of asthmatics. Results Eosinophilic (≥3%) and neutrophilic (≥76%) airway inflammation were observed in 46% and 18% of patients respectively. Predictors of sputum eosinophilia ≥3% were high blood eosinophils, FENO and IgE level and low FEV1/FVC. The derived equation was validated with a Cohen’s kappa coefficient of 0.59 (p<0.0001). ROC curves showed a cut-off value of 220/mm³ (AUC=0.79, p<0.0001) or 3% (AUC=0.81, p<0.0001) for blood eosinophils to identify sputum eosinophilia ≥3%. Independent predictors of sputum Neutrophilia were advanced age and high FRC but not blood neutrophil count. Conclusion: Eosinophilic and paucigranulocytic asthma are the dominant inflammatory phenotypes. Blood eosinophils provide a practical alternative to predict sputum eosinophilia but sputum neutrophil count is poorly related to blood neutrophils.
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distribution of sputum cellular phenotype in a large asthma cohort predicting factors for eosinophilic vs neutrophilic inflammation
BMC Pulmonary Medicine, 2013Co-Authors: Florence Schleich, Monique Henket, Maïté Manise, Jocelyne Sele, Laurence Seidel, Renaud LouisAbstract:Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors of sputum inflammatory phenotypes according to easily available clinical characteristics. This retrospective study was conducted in 508 asthmatics with successful sputum induction recruited from the University Asthma Clinic of Liege. Receiver-operating characteristic (ROC) curve and multiple logistic regression analysis were used to assess the relationship between sputum eosinophil or neutrophil count and a set of covariates. Equations predicting sputum eosinophils and neutrophils were then validated in an independent group of asthmatics. Eosinophilic (≥3%) and neutrophilic (≥76%) airway inflammation were observed in 46% and 18% of patients respectively. Predictors of sputum eosinophilia ≥3% were high blood eosinophils, FENO and IgE level and low FEV1/FVC. The derived equation was validated with a Cohen’s kappa coefficient of 0.59 (p < 0.0001). ROC curves showed a cut-off value of 220/mm3 (AUC = 0.79, p < 0.0001) or 3% (AUC = 0.81, p < 0.0001) for blood eosinophils to identify sputum eosinophilia ≥3%. Independent predictors of sputum Neutrophilia were advanced age and high FRC but not blood neutrophil count. Eosinophilic and paucigranulocytic asthma are the dominant inflammatory phenotypes. Blood eosinophils provide a practical alternative to predict sputum eosinophilia but sputum neutrophil count is poorly related to blood neutrophils.
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local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease
Cytokine, 2011Co-Authors: Catherine Moermans, Monique Henket, Maïté Manise, Jocelyne Sele, Vincent Heinen, M Nguyen, Jeanlouis Corhay, Renaud LouisAbstract:Abstract Background Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also features systemic inflammation. The purpose of our study was to compare airway and systemic inflammation in COPD to that seen in healthy subjects and to relate the inflammation with the disease severity. Methods Ninety-five COPD patients, encompassing the whole severity spectrum of the disease, were recruited from our outpatient clinic and rehabilitation center and compared to 33 healthy subjects. Induced sputum and blood samples were obtained for measurement of inflammatory cell count. Interleukin (IL)-4, IL-6, IL-10, TNF-α and IFN-γ produced by 24 h sputum and blood cell cultures were measured. Results Compared to healthy subjects, COPD exhibited a prominent airway neutrophilic inflammation associated with a marked IL-10, IL-6 and TNF-α release deficiency that contrasted with a raised IFN-γ production. Neutrophilic inflammation was also prominent at blood level together with raised production of IFN-γ, IL-10 and TNF-α. Furthermore, sputum Neutrophilia correlated with disease severity assessed by GOLD stages. Likewise the extent of TNF-α release from blood cells also positively correlated with the disease severity but negatively with that of sputum cell culture. Blood release of TNF-α and IL-6 negatively correlated with body mass index. Altogether, our results showed a significant relationship between cellular marker in blood and sputum but poor relationship between local and systemic release of cytokines. Conclusions COPD is characterized by prominent neutrophilic inflammation and raised IFN-γ production at both bronchial and systemic level. Overproduction of TNF-α at systemic level correlates with disease severity and inversely with body mass index.
Eric Deutsch - One of the best experts on this subject based on the ideXlab platform.
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Neutrophilia as prognostic biomarker in locally advanced stage iii lung cancer
PLOS ONE, 2018Co-Authors: Antoine Schernberg, Alexandre Escande, Laura Mezquita, A Boros, A Botticella, C Caramella, Benjamin Besse, David Planchard, Cecile Le Pechoux, Eric DeutschAbstract:Objective To study the prognostic value of baseline leukocytosis or Neutrophiliain two retrospective cohorts of stage III Non-Small Cell Lung Cancer (NSCLC) patients. Materials and methods Clinical records of consecutive previously untreated NSCLC patients in our Institution between June 2001 and September 2016 for stage III NSCLC were collected. The prognostic value of pretreatment leucocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and Neutrophilia were defined as a leukocyte count or a neutrophil count exceeding 10 and 7 G/L, respectively. Results We identified 238 patients, displaying baseline leukocytosis or Neutrophilia in 39% and 40% respectively. Most were diagnosed with adenocarcinoma (48%), and stage IIIB NSCLC (58%). 3-year actuarial overall survival (OS) and progression-free survival (PFS) were 35% and 27% respectively. Local relapses were reported in 100 patients (42%), and distant metastases in 132 patients (55%). In multivariate analysis, leukocytosis, Neutrophilia, and induction chemotherapy regimen based on carboplatin/paclitaxel were associated with worse OS and PFS (p<0.05). Neutrophilia independently decreased Locoregional Control (LRC) (HR = 2.5, p<0.001) and Distant Metastasis Control (DMC) (HR = 2.1, p<0.001). Neutrophilia was significantly associated with worse brain metastasis control (p = 0.004), mostly in adenocarcinoma patients (p<0.001). Conclusion In stage III NSCLC patients, treated with concurrent cisplatin-based chemoradiation, baseline leukocytosis and Neutrophilia were associated with worse OS, PFS, LRC, and DMC. In addition with previously available markers, this independent cost-effective biomarker could help to stratify stage III NSCLC population with more accuracy.
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Neutrophilia as a biomarker for overall survival in newly diagnosed high grade glioma patients undergoing chemoradiation
Clinical and Translational Radiation Oncology, 2017Co-Authors: Antoine Schernberg, Alexandre Escande, Eric Deutsch, Alexandre Nivet, Frederic Dhermain, Samy Ammari, Johan Pallud, G LouvelAbstract:Abstract Objective To study the prognostic value of neutrophil disorders in a retrospective cohort of high-grade glioma patients receiving definitive concurrent temozolomide and radiation. Materials and methods Clinical records of consecutive patients treated in our Institution between January 2005 and December 2010 with concurrent temozolomide (75 mg/m2 daily) and radiation were collected. The prognostic value of pretreatment Neutrophilia on survival, defined as a neutrophil count exceeding 7 G/L, was examined. Results We identified 164 patients, all treated with concurrent temozolomide-based chemoradiotherapy. Initial surgery was achieved in most (75%), with resection > 90% in 55 patients (34%). Total 151 patients (92%) had glioblastoma, and 13 patients (8%) had WHO grade III glioma. Eighty-two patients (50%) displayed pretreatment Neutrophilia. Neutrophilia was not associated with concurrent or adjuvant temodal discontinuation (p > 0.3). The 2-year actuarial overall survival was 45%. Steroid consumption, i.e. 60 mg or more of daily prednisolone, increased pretreatment neutrophil count (p = 0.005). In univariate analysis, Neutrophilia was associated with worse overall survival (p = 0.019), as well as age ≥ 65 years (p = 0.009), surgical resection Conclusion In high-grade gliomas treated with concurrent temozolomide and radiation, pretreatment Neutrophilia may be a significant prognosis factor for overall survival. In addition with previously available markers, this independent cost-effective biomarker could help identifying patients with worsened prognosis.
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leukocytosis and Neutrophilia predicts outcome in anal cancer
Radiotherapy and Oncology, 2017Co-Authors: Antoine Schernberg, Alexandre Escande, Eric Deutsch, Eleonor Rivin Del Campo, Michel Ducreux, Diane Goere, Cyrus ChargariAbstract:Abstract Objective Leukocytosis and Neutrophilia could be the tip of the iceberg in the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a cohort of patients treated with definitive chemoradiation for anal squamous cell carcinoma (SCC). Materials & methods Clinical records from all consecutive patients treated in a single institution between 2006 and 2016 with curative-intent radiotherapy were retrospectively analyzed. Leukocytosis and Neutrophilia, defined as leukocyte or neutrophil count over 10,000 and 7500/mm 3 , respectively, were studied in terms of overall survival (OS), progression (PFS), locoregional (LFS) and distant (DFS)-free survival. Results We identified 103 non-metastatic HIV-negative patients, with concurrent chemotherapy use in 78%. Twelve and 8% displayed baseline leukocytosis and Neutrophilia, respectively. Estimated 3-year OS and PFS were 88% and 67%, respectively. In univariate analysis, both leukocytosis and Neutrophilia were strongly associated with inferior OS, PFS, LFS and DFS ( p p Conclusion Leukocytosis and Neutrophilia are strong prognostic factors for OS, PFS, LFS and DFS in anal cancer treated with chemoradiation. These biomarkers could help identify patients with higher risk of tumor relapse that require treatment intensification.
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Neutrophilia in locally advanced cervical cancer a novel biomarker for image guided adaptive brachytherapy
Oncotarget, 2016Co-Authors: Alexandre Escande, C Haiemeder, Pierre Maroun, Sebastien Gouy, R Mazeron, T Leroy, Enrica Bentivegna, Philippe Morice, Eric DeutschAbstract:// Alexandre Escande 1 , Christine Haie-Meder 1 , Pierre Maroun 1, 2 , Sebastien Gouy 3 , Renaud Mazeron 1 , Thomas Leroy 4 , Enrica Bentivegna 3 , Philippe Morice 2, 3, 5 , Eric Deutsch 1, 2, 5 , Cyrus Chargari 1, 2, 5, 6, 7 1 Radiotherapy department, Brachytherapy Unit, Gustave Roussy Cancer Campus, Villejuif, France 2 Faculte de medecine PARIS Sud, universite Paris Sud, Universite Paris Saclay, France 3 Department of Surgery, Gustave Roussy, Villejuif, France 4 Radiotherapy Department, Oscar Lambret Comprehensive Cancer Center, Lille, France 5 INSERM1030, Gustave Roussy Cancer Campus, Villejuif, France 6 French Military Health Services Academy, Ecole du Val-de-Grâce, Paris, France 7 Institut de Recherche Biomedicale des Armees, Bretigny-sur-Orge, France Correspondence to: Cyrus Chargari, email: cyrus.chargari@gustaveroussy.fr Keywords: locally advanced cervical cancer, image-guided adaptive brachytherapy, prognostic factor, biomarkers, Neutrophilia Received: June 27, 2016 Accepted: September 19, 2016 Published: October 04, 2016 ABSTRACT Objective: To study the prognostic value of leucocyte disorders in a prospective cohort of cervical cancer patients receiving definitive chemoradiation plus image—guided adaptive brachytherapy (IGABT). Results: 113 patients were identified. All patients received a pelvic irradiation concomitant with chemotherapy, extended to the para-aortic area in 13 patients with IVB disease. Neutrophilia and leukocytosis were significant univariate prognostic factors for poorer local failure-free survival ( p = 0.000 and p = 0.002, respectively), associated with tumor size, high-risk clinical target volume (HR-CTV) and anemia. No effect was shown for distant metastases but leukocytosis and neutrophila were both poor prognostic factors for in-field relapses ( p = 0.003 and p 7,500/μl ( p = 0.018) were independent factors for poorer survival without local failure, with hazard ratio (HR) of 3.1. Materials and methods: We examined patients treated in our Institution between April 2009 and July 2015 by concurrent chemoradiation (45 Gy in 25 fractions +/– lymph node boosts) followed by a magnetic resonance imaging (MRI)-guided adaptive pulse-dose rate brachytherapy (15 Gy to the intermediate-risk clinical target volume). The prognostic value of pretreatment leucocyte disorders was examined. Leukocytosis and Neutrophilia were defined as a leukocyte count or a neutrophils count exceeding 10,000 and 7,500/μl, respectively. Conclusions: Neutrophilia is a significant prognostic factor for local relapse in locally advanced cervical cancer treated with MRI-based IGABT. This biomarker could help identifying patients with higher risk of local relapse and requiring dose escalation.
H Jones - One of the best experts on this subject based on the ideXlab platform.
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comparison of pde 4 inhibitors rolipram and sb 207499 ariflotm in a rat model of pulmonary Neutrophilia
Pulmonary Pharmacology & Therapeutics, 2001Co-Authors: J Spond, Richard W Chapman, Jay S Fine, H Jones, William Kreutner, Ted T Kung, Michael MinnicozziAbstract:Abstract Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose–response experiments, we found that rats exposed to 10 μg or 100 μg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary Neutrophilia, provoked by the challenge of 10 μg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 μg LPS caused the local pulmonary production of TNF- α . In contrast to the cellular influx, TNF- α production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 β in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- α and IL-1 β was unaffected by either SB 207499 or rolipram. When provoked with the 10 μg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary Neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- α or the inhibition of IL-1 β , and occur independently of endogenous catecholamine or corticosteroid release.
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comparison of pde 4 inhibitors rolipram and sb 207499 ariflotm in a rat model of pulmonary Neutrophilia
Pulmonary Pharmacology & Therapeutics, 2001Co-Authors: J Spond, Richard W Chapman, Jay S Fine, H Jones, William Kreutner, Ted T Kung, Michael MinnicozziAbstract:Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose-response experiments, we found that rats exposed to 10 microg or 100 microg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary Neutrophilia, provoked by the challenge of 10 microg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 microg LPS caused the local pulmonary production of TNF- alpha. In contrast to the cellular influx, TNF- alpha production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 beta in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- alpha and IL-1 beta was unaffected by either SB 207499 or rolipram. When provoked with the 10 microg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary Neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- alpha or the inhibition of IL-1 beta, and occur independently of endogenous catecholamine or corticosteroid release.