RESUMO
PURPOSE: Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described. PATIENTS AND METHODS: A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed. RESULTS: Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14-336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19-1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38-90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01-0.35; P = 0.01). CONCLUSIONS: DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.
Assuntos
Antineoplásicos/efeitos adversos , Doenças Pulmonares Intersticiais/epidemiologia , Pulmão/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Idoso , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Incidência , Pulmão/efeitos dos fármacos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Fatores de TempoRESUMO
OBJECTIVES: We hypothesised that it was possible to quantify phosphorylation of important nodes in the phosphatidylinositol 3-kinase (PI3K) pathway in cancer cells isolated from pleural effusions of patients with non-small cell lung cancer (NSCLC) and study their correlation to somatic mutations and clinical outcomes. MATERIALS AND METHODS: Cells were immunomagnetically separated from samples of pleural effusion in patients with NSCLC. p-AKT, p-S6K and p-GSK3ß levels were quantified by ELISA; targeted next-generation sequencing was used to characterise mutations in 26 genes. RESULTS: It was possible to quantify phosphoproteins in cells isolated from 38/43 pleural effusions. There was a significant correlation between p-AKT and p-S6K levels [r = 0.85 (95% confidence interval 0.73-0.92), p < 0.0001], but not p-AKT and p-GSK3ß levels [r = 0.19 (95% confidence interval -0.16 to 0.5), p = 0.3]. A wide range of mutations was described and p-S6K was higher in samples that harboured at least one mutation compared to those that did not (p = 0.03). On multivariate analysis, p-S6K levels were significantly associated with poor survival (p < 0.01). CONCLUSION: Our study has shown a correlation between p-AKT levels and p-S6K, but not GSK3ß, suggesting differences in regulation of the distal PI3K pathway by AKT. Higher p-S6K levels were associated with adverse survival, making it a critically important target in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Derrame Pleural Maligno/patologia , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Células Neoplásicas Circulantes/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismoRESUMO
Asthma and chronic obstructive pulmonary disease (COPD) are associated with Th2 and Th1 differentiated T cells. The cytokine thymic stromal lymphopoietin (TSLP) promotes differentiation of Th2 T cells and secretion of chemokines which preferentially attract them. We hypothesized that there is distinct airways expression of TSLP and chemokines which preferentially attract Th1- and Th2-type T cells, and influx of T cells bearing their receptors in asthma and COPD. In situ hybridization, immunohistochemistry, and ELISA were used to examine the expression and cellular provenance of TSLP, Th2-attracting (TARC/CCL17, MDC/CCL22, I-309/CCL1), and Th1-attracting (IP-10/CXCL10, I-TAC/CXCL11) chemokines in the bronchial mucosa and bronchoalveolar lavage fluid of subjects with moderate/severe asthma, COPD, and controls. Cells expressing mRNA encoding TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in severe asthma and COPD as compared with non-smoker controls (p < 0.02). This pattern was reflected in bronchoalveolar lavage fluid protein concentrations. Expression of the same chemokines was also increased in ex- and current smokers. The cellular sources of TSLP and chemokines were strikingly similar in severe asthma and COPD. The numbers of total bronchial mucosal T cells expressing the chemokine receptors CCR4, CCR8, and CXCR3 did not significantly differ in asthma, COPD, and controls. Both asthma and COPD are associated with elevated bronchial mucosal expression of TSLP and the same Th1- and Th2-attracting chemokines. Increased expression of these chemokines is not, however, associated with selective accumulation of T cells bearing their receptors.
Assuntos
Asma/imunologia , Asma/metabolismo , Quimiocinas/biossíntese , Quimiotaxia de Leucócito/imunologia , Citocinas/biossíntese , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Timo/imunologia , Proteínas ADAM/biossíntese , Adulto , Idoso , Asma/patologia , Quimiocina CCL1/biossíntese , Quimiocina CCL17/biossíntese , Quimiocina CXCL10/biossíntese , Quimiocina CXCL11/biossíntese , Quimiocinas/genética , Citocinas/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Índice de Gravidade de Doença , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia , Timo/metabolismo , Timo/patologia , Proteínas Supressoras de Tumor/biossíntese , Linfopoietina do Estroma do TimoRESUMO
Glucose concentrations of normal human airway surface liquid are approximately 12.5 times lower than blood glucose concentrations indicating that glucose uptake by epithelial cells may play a role in maintaining lung glucose homeostasis. We have therefore investigated potential glucose uptake mechanisms in non-polarised and polarised H441 human airway epithelial cells and bronchial biopsies. We detected mRNA and protein for glucose transporter type 2 (GLUT2) and glucose transporter type 4 (GLUT4) in non-polarised cells but GLUT4 was not detected in the plasma membrane. In polarised cells, GLUT2 protein was detected in both apical and basolateral membranes. Furthermore, GLUT2 protein was localised to epithelial cells of human bronchial mucosa biopsies. In non-polarised H441 cells, uptake of D: -glucose and deoxyglucose was similar. Uptake of both was inhibited by phloretin indicating that glucose uptake was via GLUT-mediated transport. Phloretin-sensitive transport remained the predominant route for glucose uptake across apical and basolateral membranes of polarised cells and was maximal at 5-10 mM glucose. We could not conclusively demonstrate sodium/glucose transporter-mediated transport in non-polarised or polarised cells. Our study provides the first evidence that glucose transport in human airway epithelial cells in vitro and in vivo utilises GLUT2 transporters. We speculate that these transporters could contribute to glucose uptake/homeostasis in the human airway.
Assuntos
Polaridade Celular , Células Epiteliais , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Mucosa Respiratória/citologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Homeostase , Humanos , Florizina/metabolismoRESUMO
BACKGROUND: Overexpression of the transcriptional regulatory factor activator protein 1 might contribute to T-cell glucocorticoid (GC) refractoriness in GC-resistant asthma. OBJECTIVE: We sought to address the hypothesis that clinically GC-resistant asthma is accompanied by failure of systemic GCs to inhibit phosphorylation of c-jun and c-jun N-terminal kinase (JNK) in bronchial mucosal cells. METHODS: We performed enumeration of total (CD45+) leukocytes and cells expressing c-fos and total and phosphorylated c-jun and JNK in bronchial biopsy sections from 9 GC-sensitive and 17 GC-resistant asthmatic patients taken before and after oral prednisolone (40 mg/1.72 m(2) body surface area daily for 14 days) using specific antibodies, immunohistochemistry, and image analysis. RESULTS: At baseline, mean total (CD45+) mucosal leukocytes, total cells expressing phosphorylated c-jun and JNK, and mean percentages of cells in which these molecules were phosphorylated were similar in both groups, whereas mean total numbers of c-fos-immunoreactive cells were increased in the GC-resistant asthmatic subjects (P = .04). After prednisolone, the mean total cells expressing phosphorylated c-jun and JNK and the mean percentages of cells in which these molecules were phosphorylated were significantly reduced in the GC-sensitive (P < or = .02) but not the GC-resistant asthmatic subjects. Mean total CD45+ leukocytes and c-fos-immunoreactive cells were not significantly altered in either group. CONCLUSION: Clinical GC responsiveness in asthma is accompanied by reduced phosphorylation of bronchial mucosal c-jun and JNK, a phenomenon not seen in resistant patients. CLINICAL IMPLICATIONS: Dysregulation of activator protein 1 activation leading to clinical GC resistance might reflect identifiable environmental influences and is a target for future therapy.
Assuntos
Asma/metabolismo , Resistência a Medicamentos , Glucocorticoides/uso terapêutico , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Prednisolona/uso terapêutico , Fator de Transcrição AP-1/metabolismo , Asma/tratamento farmacológico , Asma/imunologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Antígenos Comuns de Leucócito/imunologia , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismoRESUMO
RATIONALE: Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with fibronectin and collagen are key features of asthma. Previously, we have reported these ECM proteins enhance ASM synthetic function. OBJECTIVE: We compared ASM cultured from endobronchial biopsies from subjects with and without asthma to assess if asthmatic cells were hypersecretory and determined whether the underlying mechanism involved autocrine ECM production. METHODS AND MEASUREMENTS: Cells from subjects with and without asthma were cultured on plastic or in plates precoated with ECM proteins. Cytokine production was evaluated by enzyme-linked immunosorbent assay and by reverse transcriptase-polymerase chain reaction. Function-blocking integrin antibodies were used to identify integrin involvement. RESULTS: Baseline eotaxin and its production after stimulation with interleukin (IL)-13, IL-1beta, or tumor necrosis factor-alpha was increased (2.5- to 6.0-fold) in ASM cells cultured from subjects with asthma compared with healthy subjects. When seeded on ECM from asthmatic ASM, IL-13-dependent eotaxin release from healthy or asthmatic ASM was enhanced compared with culture on healthy ECM. The ECM substrates fibronectin and type I collagen each enhanced IL-13-dependent eotaxin release, and Western immunoblot indicated that fibronectin expression was higher in asthmatic ASM cells. Integrin-blocking antibodies revealed that alpha5beta1 was required for more than 50% of the enhanced IL-13-dependent eotaxin release by ASM cells from subjects with asthma, whereas alpha2beta1 or alphavbeta3 neutralization lacked effect. CONCLUSION: The data indicate that ASM cells cultured from subjects with asthma are hypersecretory compared with cells from healthy donors and that autocrine fibronectin secretion acting via alpha5beta1 in part underlies this effect.