ABSTRACT
Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1(-/-) mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.
Subject(s)
Idiopathic Pulmonary Fibrosis/immunology , Interleukin-13 Receptor alpha1 Subunit/immunology , Interleukin-13/immunology , Lung Injury/immunology , Adult , Animals , Bleomycin , Case-Control Studies , Female , Gene Expression Regulation , Homeostasis/immunology , Humans , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Interleukin-13/genetics , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Lung/immunology , Lung/pathology , Lung Injury/chemically induced , Lung Injury/genetics , Lung Injury/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Protein Isoforms/genetics , Protein Isoforms/immunology , Receptors, Interleukin-4/genetics , Receptors, Interleukin-4/immunology , Signal Transduction , Transcription, GeneticABSTRACT
The aim of this study was to establish an ex vivo model for a faster optimisation of sample preparation procedures, for example matrix choice, in matrix-assisted laser desorption/ionisation (MALDI) drug imaging studies. The ionisation properties of four drugs, afatinib, erlotinib, irinotecan and pirfenidone, were determined in an ex vivo tissue experiment by spotting decreasing dilution series onto liver sections. Hereby, the drug signals were distinctly detectable using different matrix compounds, which allowed the selection of the optimal matrix for each drug. The analysis of afatinib and erlotinib yielded high drug signals with α-cyano-4-hydroxycinnamic acid matrix, whereas 2,3-dihydroxybenzoic acid was identified as optimal matrix for irinotecan and pirfenidone detection. Our method was validated by a MALDI drug imaging approach of in vivo treated mouse tissue resulting in corresponding findings, indicating the spotting method as an appropriate approach to determine the matrix of choice. The present study shows the accordance between the detection of ex vivo spotted drugs and in vivo administered drugs by MALDI-TOF and MALDI-FT-ICR imaging, which has not been demonstrated so far. Our data suggest the ex vivo tissue spotting method as an easy and reliable model to optimise MALDI imaging measurements and to predict drug detection in tissue sections derived from treated mice prior to the recruitment of laboratory animals, which helps to save animals, time and costs.
Subject(s)
Camptothecin/analogs & derivatives , Liver/chemistry , Models, Animal , Pyridones/analysis , Quinazolines/analysis , Administration, Intravenous , Administration, Oral , Afatinib , Animals , Camptothecin/administration & dosage , Camptothecin/analysis , Erlotinib Hydrochloride , In Vitro Techniques , Irinotecan , Mice , Mice, Inbred C57BL , Mice, Nude , Molecular Structure , Pyridones/administration & dosage , Quinazolines/administration & dosage , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
INTRODUCTION: The objective of this study was to determine the prevalence of family history of colorectal cancer (CRC) in a population between 40 and 75 years-old, as well as acceptability and early diagnosis tests made. MATERIAL AND METHODS: Cross-sectional study. LOCATION: El Coto and El Llano (Gijon) primary care health centres. A total of 800 individuals aged between 40 and 75 years participated, selected by simple random sampling. Key measurements: questionnaire conducted by telephone with previous notice by newsletter. The variables studied were: family history (FH) of CRC, age at diagnosis, performance of faecal occult blood test (FOBT)/colonoscopy, reason for doing it or refusing it, and sociodemographic data. RESULTS: A total of 664 questionnaires were valid. The prevalence of FH was 15.8% (confidence interval 12.9 to 18.6), with 8.8% with at least one first degree relative. An FOBT screening had been performed on 7.1%, and 17.9% had undergone colonoscopies, mostly on clinical grounds. Acceptability was 90.7% for FOBT and 65.2% for colonoscopy. Main reason for the refusal of an FOBT was the belief that early diagnosis would not alter prognosis. Main reason for rejection of colonoscopy was discomfort or fear of the test. CONCLUSIONS: There was a low rate of testing for FH, and a high acceptability for FOBT and a low acceptability for colonoscopy. Aspects affecting the general population (causes for rejection, need for clear information), as well as a correct coordination between Primary Care, specialized care, and public health, need to be reviewed.
