RESUMO
BACKGROUND: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. METHODS: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences. RESULTS: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. CONCLUSIONS: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.).
Assuntos
Asma , Humanos , Estudos de Coortes , Japão/epidemiologia , Asma/diagnóstico , Asma/epidemiologia , Asma/tratamento farmacológico , Fenótipo , Biomarcadores , Análise por ConglomeradosRESUMO
BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is rare, but potentially life threatening owing to respiratory failure. However, knowledge is limited about the condition of hospitalized LAM patients. The objectives of this study were to investigate patient characteristics, comorbidities and causes of death among hospitalized LAM patients in Japan. METHODS: Using a national inpatient database in Japan, information on 280 LAM patients hospitalized between July 2010 and March 2013 was retrospectively collected. We divided the 280 patients into three groups according to their status regarding lung transplantation. RESULTS: For the study period, we identified 32 patients who had undergone lung transplantation ('after-transplantation' group), 12 patients admitted for lung transplantation ('for-transplantation') and 236 patients who had not undergone transplantation ('no-transplantation'). Although the clinical features of LAM patients in the 'no-transplantation' group were similar to previously reported findings, patients hospitalized in connection with transplantation showed the following: the activities of daily living score using the Barthel Index in the 'after-transplantation' group (89.4) was significantly higher than in the 'for-transplantation' group (64.6); the mortality rates in the after-transplantation group (3.1%) were significantly lower than in the for-transplantation group (25%). The most frequent comorbidity was pneumothorax, followed by respiratory failure and angiomyolipoma, although there was no significant difference in the prevalence among the three groups. CONCLUSIONS: We determined the clinical features, comorbidities and fatalities in hospitalized LAM patients. Patients with LAM after transplantation had higher activities of daily living scores than those before transplantation, which suggests that lung transplantation may improve activities of daily living.
Assuntos
Neoplasias Pulmonares , Transplante de Pulmão , Linfangioleiomiomatose , Atividades Cotidianas , Adulto , Idoso , Causas de Morte , Comorbidade , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Japão/epidemiologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/cirurgia , Transplante de Pulmão/métodos , Transplante de Pulmão/reabilitação , Linfangioleiomiomatose/epidemiologia , Linfangioleiomiomatose/patologia , Linfangioleiomiomatose/fisiopatologia , Linfangioleiomiomatose/cirurgia , Masculino , Pessoa de Meia-Idade , Pneumotórax/epidemiologia , Pneumotórax/etiologia , Prevalência , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVE: Obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), have airflow limitation associated with chronic inflammation. Using a national inpatient database in Japan, we aimed to evaluate factors affecting in-hospital mortality in patients with asthma, COPD or asthma-COPD overlap (ACO). METHODS: We retrospectively collected data for inpatients (age >40 years) with exacerbation of COPD and/or asthma in 1073 hospitals across Japan between July 2010 and May 2013. We performed multivariable logistic regression analysis to examine the association of various factors with all-cause in-hospital mortality, including diagnosis of ACO, asthma alone and COPD alone. RESULTS: Of 30 405 eligible patients, in-hospital mortality in patients with ACO, asthma alone and COPD alone was 2.3%, 1.2% and 9.7%, respectively. COPD patients had a significantly higher mortality than ACO patients (odds ratio 1.96; 95% confidence interval: 1.38-2.79); patients with asthma alone showed lower mortality (0.70; 0.50-0.97). Higher mortality was also significantly associated with older age, male gender, lower body mass index, more severe dyspnoea, lower level of consciousness, worse activities of daily life and higher daily dose of corticosteroids. CONCLUSION: Asthma alone was associated with lower mortality, but COPD alone was associated with higher mortality than ACO.
Assuntos
Asma/mortalidade , Mortalidade Hospitalar , Doença Pulmonar Obstrutiva Crônica/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/fisiopatologia , Índice de Massa Corporal , Comorbidade , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients often have dysphagia through age and several co-morbidities, leading to aspiration pneumonia (AsP). COPD patients also have increased risk of developing community-acquired pneumonia (CAP). Using a national inpatient database in Japan, we aimed to compare clinical characteristics and outcomes between AsP and CAP in COPD patients and to verify the factors that affect in-hospital morality. METHODS: We retrospectively collected data on COPD patients (age ≥40 years) who were admitted for AsP or CAP in 1,165 hospitals across Japan between July 2010 and May 2013. We performed multivariable logistic regression analyses to examine the association of various factors with all-cause in-hospital mortality for AsP and CAP. RESULTS: Of 87,330 eligible patients, AsP patients were more likely to be older, male and have poorer general condition and more severe pneumonia than those with CAP. In-hospital mortality in the AsP group was 22.7% and 12.2% in the CAP group. After adjustment for patient background, AsP patients had significantly higher mortality than CAP patients (adjusted odds ratio, 1.19; 95% confidence interval, 1.08-1.32). Subgroup analyses showed higher mortality to be associated with male gender, underweight, dyspnea, physical disability, pneumonia severity, and several co-morbidities. Further, older age and worse level of consciousness were associated with higher mortality in the CAP group, whereas those were not associated in the AsP group. CONCLUSIONS: Clinical characteristics differed significantly between AsP and CAP in COPD patients. AsP patients had significantly higher mortality than those with CAP.
Assuntos
Infecções Comunitárias Adquiridas/mortalidade , Pneumonia Aspirativa/mortalidade , Doença Pulmonar Obstrutiva Crônica/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Comorbidade , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Estudos RetrospectivosRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide. Patients with COPD frequently have systemic comorbidities that often require unscheduled hospitalization for exacerbation and deterioration of physical conditions, and can have a poor prognosis. We verified factors affecting patients' short-term mortality, using a national inpatient database in Japan. METHODS: We retrospectively collected data for COPD patients (age: >40 years) with emergency admission between July 2010 and March 2013, using the Diagnosis Procedure Combination database. We performed multivariate logistic analyses fitted with a generalized estimating equation to assess factors associated with all-cause in-hospital mortality. RESULTS: A total of 177,207 patients (mean age: 77.5 years; males: 72.9%) were identified. All-cause in-hospital death occurred in 23,614 patients (13.7%). Higher mortality was associated with older age, male sex, lower body mass index, more severe dyspnea, lower level of consciousness, and worse activities of daily life. Higher mortality was also associated with comorbid conditions, including bacterial pneumonia, aspiration pneumonia, interstitial pneumonitis, pulmonary embolism, respiratory failure, lung cancer, heart failure, cerebral infarction, liver cirrhosis, and chronic renal failure. CONCLUSIONS: Our study demonstrated that all-cause in-hospital mortality in patients with COPD who required emergency hospitalization was associated with deteriorated general conditions and comorbidities at admission. Physicians should take into account these prognostic factors to choose better treatment options for COPD patients.
Assuntos
Mortalidade Hospitalar , Doença Pulmonar Obstrutiva Crônica/mortalidade , Atividades Cotidianas , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Comorbidade , Transtornos da Consciência/etiologia , Dispneia/etiologia , Emergências , Feminino , Hospitalização , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Estudos Retrospectivos , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND: Airway remodeling is an important feature of chronic airway disease, but the mechanisms involved remain unclear. Recently, epithelial mesenchymal transition (EMT) was reported to be associated with tissue fibrosis. TGF-ß1, which is a potent inducer of EMT, is thought to be related to the pathogenesis of airway remodeling. We investigated whether TGF-ß1 and/or TNF-α induce EMT in bronchial epithelial cells. METHODS: Cultured BEAS-2B cells and primary normal human bronchial epithelial cells (NHBE) were treated with TGF-ß1 and/or TNF-α. Morphological changes and the expression of EMT-related markers were evaluated by immunocytochemical staining. Expressions of EMT-related markers, extracellular matrix (ECM) components (collagen type I and versican), and TGF-ß receptors I, II, and III were analyzed by quantitative RT-PCR. Migration was evaluated using the Boyden chamber technique. RESULTS: The TGF-ß1-induced EMT in BEAS-2B cells was demonstrated on the basis of morphological changes and the downregulation of E-cadherin. Costimulation with TNF-α enhanced the TGF-ß1-induced morphological changes and increased vimentin expression. Treatment with TGF-ß1 increased the expression of collagen type I and versican. EMT induced with TGF-ß1 plus TNF-α promoted cell migration. Stimulation of NHBE with TGF-ß1 led to EMT. CONCLUSION: TGF-ß1 induced EMT in BEAS-2B cells, and costimulation with TNF-α enhanced the EMT. As a result of the EMT process, BEAS-2B cells acquired functions of mesenchymal cells. In addition, TGF-ß1 treatment induced EMT in NHBE as shown by changes in EMT-related markers. Bronchial epithelial cells might contribute to airway remodeling through EMT.
Assuntos
Brônquios/citologia , Células Epiteliais/metabolismo , Receptor Cross-Talk , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Remodelação das Vias Aéreas , Biomarcadores/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Transformada , Movimento Celular/imunologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Células Epiteliais/citologia , Células Epiteliais/imunologia , Transição Epitelial-Mesenquimal/imunologia , Humanos , Receptor Cross-Talk/imunologia , Fator de Crescimento Transformador beta/imunologia , Fator de Necrose Tumoral alfa/imunologia , Versicanas/genética , Versicanas/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMO
Recently, epithelial-mesenchymal transition (EMT) has been reported to contribute to tissue fibrosis through enhanced transforming growth factor (TGF)-beta1 signaling. Tumor necrosis factor (TNF)-alpha has also been implicated in tissue fibrosis. Therefore, the authors investigated whether TNF-alpha affected TGF-beta1-induced EMT. Cultured alveolar epithelial cells (A549 cells) were stimulated with TGF-beta1 (5 ng/mL), with/without TNF-alpha (10 ng/mL). TGF-beta1 induced EMT of A549 cells, with loss of E-cadherin and acquisition of vimentin. Combination of TNF-alpha with TGF-beta1 enhanced EMT, causing morphological changes, while quantitative polymerase chain reaction (PCR) showed suppression of E-cadherin mRNA and expression of vimentin mRNA. In addition, the gel contraction method revealed that cells that had undergone EMT acquired cell contractility, which is a feature of mesenchymal cells. Stimulation with TGF-beta1 induced cell contraction, as did TNF-alpha. Moreover, costimulation with TGF-beta1 and TNF-alpha enhanced the cell contraction. Although IFN-gamma suppressed spontaneous cell contraction, it did not suppress cell contraction, which was induced by TGF-beta1. In conclusion, TNF-alpha enhances not only EMT but also cell contraction induced by TGF-beta1. EMT might contribute to tissue fibrosis through induction of cell contraction.
Assuntos
Adenocarcinoma Bronquioloalveolar/patologia , Desdiferenciação Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Fibrose/etiologia , Humanos , Células-Tronco Mesenquimais/patologiaRESUMO
C-reactive protein (CRP) has been classically used as a marker of inflammation. The aim of this study was to investigate the effect of CRP on migration of human fetal lung fibroblasts (HFL-1) to human plasma fibronectin (HFn). Using the blindwell chamber technique, CRP inhibited HFL-1 migration in a dose-dependent fashion (at 1 microg/mL, inhibition: 32.5% +/- 7.1%; P < .05). Western blot analysis showed that CRP inhibited the p38 mitogen-activated protein kinase (MAPK) activity in the presence of HFn. Moreover, the MAPK inhibitors SB202190 (25 microM) and SB203580 (25 microM) inhibited HFn-induced cell migration, suggesting an important role of p38 MAPK in HFn-induced migration. Taken together, these results suggest that the inhibitory effect of CRP is mediated by blocking MAPK. In summary, this study demonstrates that CRP directly modulates human lung fibroblasts migration. Thus, CRP may contribute to regulation of wound healing and may be endogenous antifibrotic factor acting on lung fibrosis.
Assuntos
Proteína C-Reativa/farmacologia , Inibição de Migração Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Ensaios de Migração Celular , Inibição de Migração Celular/fisiologia , Células Cultivadas , Quimiotaxia/fisiologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Humanos , Imidazóis/farmacologia , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Piridinas/farmacologia , Azida Sódica/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
We herein describe a patient with Behçet's disease in whom we followed the development and resolution of pulmonary artery aneurysms. He presented with intermittent hemoptysis, pulmonary thromboembolism was initially diagnosed, and anticoagulant therapy was started. Over the next several months, the expansion of pulmonary arteries was noted. Five months after his initial admission, he was readmitted for massive hemoptysis, and further examinations revealed that he had Behçet's disease. Corticosteroids and intravenous cyclophosphamide were started. Over the next five months, the pulmonary artery aneurysms and thrombosis resolved. The development of pulmonary artery aneurysms led to the diagnosis of Behçet's disease, and they resolved after immunosuppressive therapy.
Assuntos
Aneurisma/etiologia , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Artéria Pulmonar , Embolia Pulmonar/etiologia , Adulto , Aneurisma/diagnóstico por imagem , Síndrome de Behçet/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Glucocorticoides/uso terapêutico , Hemoptise/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Embolia Pulmonar/diagnóstico por imagemRESUMO
BACKGROUND AND OBJECTIVE: The prevalence and mortality of chronic obstructive pulmonary disease (COPD) in elderly patients are increasing worldwide. Low body mass index (BMI) is a well-known prognostic factor for COPD. However, the obesity paradox in elderly patients with COPD has not been well elucidated. We investigated the association between BMI and in-hospital mortality in elderly COPD patients. METHODS: Using the Diagnosis Procedure Combination database in Japan, we retrospectively collected data for elderly patients (>65 years) with COPD who were hospitalized between July 2010 and March 2013. We performed multivariable logistic regression analysis to compare all-cause in-hospital mortality between patients with BMI of <18.5 kg/m2 (underweight), 18.5-22.9 kg/m2 (low-normal weight), 23.0-24.9 kg/m2 (high-normal weight), 25.0-29.9 kg/m2 (overweight), and ≥30.0 kg/m2 (obesity) with adjustment for patient backgrounds. RESULTS: In all, 263,940 eligible patients were identified. In-hospital mortality was 14.3%, 7.3%, 4.9%, 4.3%, and 4.4%, respectively, in underweight, low-normal weight, high-normal weight, overweight, and obese patients. Underweight patients had a significantly higher mortality than low-normal weight patients (odds ratio [OR]: 1.55, 95% confidence interval [CI]: 1.48-1.63), whereas lower mortality was associated with high-normal weight (OR: 0.76, CI: 0.70-0.82), overweight (OR: 0.73, CI: 0.66-0.80), and obesity (OR: 0.67, CI: 0.52-0.86). Higher mortality was significantly associated with older age, male sex, more severe dyspnea, lower level of consciousness, and lower activities of daily living. CONCLUSION: Overweight and obese patients had a lower mortality than low-normal weight patients, which supports the obesity paradox.
Assuntos
Índice de Massa Corporal , Mortalidade Hospitalar , Obesidade/mortalidade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Magreza/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Comorbidade , Bases de Dados Factuais , Feminino , Hospitalização , Humanos , Japão/epidemiologia , Modelos Logísticos , Masculino , Análise Multivariada , Obesidade/diagnóstico , Razão de Chances , Fatores de Proteção , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Magreza/diagnóstico , Fatores de TempoRESUMO
The epithelial surface is often proposed to actively participate in host defense, but evidence that this is the case remains circumstantial. Similarly, respiratory paramyxoviral infections are a leading cause of serious respiratory disease, but the basis for host defense against severe illness is uncertain. Here we use a common mouse paramyxovirus (Sendai virus) to show that a prominent early event in respiratory paramyxoviral infection is activation of the IFN-signaling protein Stat1 in airway epithelial cells. Furthermore, Stat1-/- mice developed illness that resembled severe paramyxoviral respiratory infection in humans and was characterized by increased viral replication and neutrophilic inflammation in concert with overproduction of TNF-alpha and neutrophil chemokine CXCL2. Poor control of viral replication as well as TNF-alpha and CXCL2 overproduction were both mimicked by infection of Stat1-/- airway epithelial cells in culture. TNF-alpha drives the CXCL2 response, because it can be reversed by TNF-alpha blockade in vitro and in vivo. These findings pointed to an epithelial defect in Stat1-/- mice. Indeed, we next demonstrated that Stat1-/- mice that were reconstituted with wild-type bone marrow were still susceptible to infection with Sendai virus, whereas wild-type mice that received Stat1-/- bone marrow retained resistance to infection. The susceptible epithelial Stat1-/- chimeric mice also exhibited increased viral replication as well as excessive neutrophils, CXCL2, and TNF-alpha in the airspace. These findings provide some of the most definitive evidence to date for the critical role of barrier epithelial cells in innate immunity to common pathogens, particularly in controlling viral replication.
Assuntos
Imunidade Inata , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Infecções por Respirovirus/imunologia , Fator de Transcrição STAT1/fisiologia , Vírus Sendai/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Interferon beta/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Respiratória/metabolismo , Infecções por Respirovirus/genética , Infecções por Respirovirus/mortalidade , Infecções por Respirovirus/patologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Índice de Gravidade de Doença , Análise de Sobrevida , Traqueia/imunologia , Traqueia/metabolismo , Traqueia/patologia , Replicação Viral/imunologiaRESUMO
A normal level of interferon (IFN) responsiveness via the Stat1 transcription factor is critical to the host, since decreased Stat1 signaling causes immune compromise and increased signaling is associated with inflammatory and neoplastic disease. Here we report how this balance may be influenced by novel alterations in the efficiency of Stat1 signaling. To enable disulfide-dependent and spontaneous formation of active Stat1 homodimer (as was done previously for Stat3), we engineered Stat1-CC with double-cysteine substitutions in the Src homology 2 (SH2)-homodimerization domain (at Ala-656 and Asn-658). In this case, however, mutant and wild-type Stat1 exhibited no difference inspontaneousdimerization. Moreover, Stat1-CC still required ligand-dependent Tyr-701 phosphorylation for function and exhibited hyperresponsiveness to IFN-beta (that depends on Stat1/Stat2 heterodimerization) as well as IFN-gamma (that depends on Stat1/Stat1 homodimerization). Hyperresponsivenss of Stat1-CC was accompanied by increased capacities for Tyr-701 phosphorylation and DNA binding, but these features were also found in a similarly substituted serine mutant (Stat1-SS) that showed no hyperresponsiveness to IFN-gamma. This finding raised the possibility that SH2 domain mutations also influence downstream transcriptional efficiency. Indeed, each of these mutations also enhanced recruitment of the normally rate-limiting p300/CREB-binding Protein (CBP) coactivator to the transcriptional complex in proportion to the level of IFN-driven transactivation and gene expression. Additional modifications indicated that the mutant residues in the SH2 domain appeared to cooperate with Ser-727 in the C-terminal domain to regulate p300/CBP interaction with Stat1. The profile of IFN responsiveness translated into the same progressive increase in the level of viral clearance from Stat1- to Stat1-SS- to Stat1-CC-expressing cells. Thus, SH2 domain determinants may be modified to direct better Stat1 phosphorylation, DNA binding, and coactivator recruitment to fully improve IFN efficacy.
Assuntos
Antineoplásicos/farmacologia , Interferon beta/farmacologia , Interferon gama/farmacologia , Fator de Transcrição STAT1/fisiologia , Proteína de Ligação a CREB/fisiologia , Cisteína , DNA/metabolismo , Proteína p300 Associada a E1A/fisiologia , Inflamação , Mutagênese Sítio-Dirigida , Fosforilação , Retroviridae , Fator de Transcrição STAT1/química , Fator de Transcrição STAT1/genética , Transdução de Sinais , Transfecção , Domínios de Homologia de srcRESUMO
Proliferation of bronchial epithelial cells is an important biologic process in a variety of physiologic and pathologic conditions. In this study, we demonstrate that hepatocyte growth factor (HGF) stimulates proliferation of human bronchial epithelial cells obtained from healthy volunteers. The mitogenic effect of HGF is dependent on costimulation with serum and is completely abrogated by interferon-gamma (IFN-gamma). In the absence of serum, HGF is capable of inducing activation of extracellular signal-regulated kinases (ERK)1 and ERK2, but fails to stimulate proliferation by itself. These effects of HGF and IFN-gamma were reproduced faithfully in BEAS-2B cells, which are an immortalized cell line derived from human bronchial epithelial cells. Further, we investigated the molecular mechanisms underlying the effects of HGF and IFN-gamma in BEAS-2B cells and found that the MEK1 inhibitor PD98059, but not the p38 M-associated protein kinase inhibitor SB203580, abrogates HGF-induced ERK activation and proliferation in response to HGF and serum. In addition, LY294002, which is the specific inhibitor of phosphatidyl inositol 3-kinase, partially inhibited HGF- and serum-stimulated proliferation. We also found that HGF by itself is capable of inducing a G1 cyclin, cyclin D1, but fails to downregulate p27(kip1) cyclin-dependent kinase (CDK) inhibitor, which is a requisite for G1 to S phase cell cycle progression. IFN-gamma does not interfere with the effects of HGF on either ERK activation or cyclin D1 induction; however, it prevents the downregulation of p27(kip1) CDK inhibitor that takes place in response to a combination of HGF and serum. These results indicate that the MEK-ERK signaling pathway is necessary but not sufficient for human bronchial epithelial cell proliferation, and implicate the significance of HGF and IFN-gamma in the repair processes of injured human bronchial epithelial cells.