tretinoin and Lung-Diseases--Obstructive

Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.

Topics: Adult; Animals; Benzoates; Cells, Cultured; Disease Models, Animal; Female; Fibrosis; Humans; Hypertrophy; Lung; Lung Diseases, Obstructive; Male; Mice; Mice, Transgenic; Muscle, Smooth; Myocytes, Smooth Muscle; Primary Cell Culture; Receptors, Retinoic Acid; Signal Transduction; Stilbenes; Tretinoin

Retinoids, such as all-trans-retinoic acid, play an essential role in the regulation of airway epithelial cell growth, differentiation, and gene expression. Using cDNA microarray, we identified a clone, DD4, that contains the cDNA of a novel gene, spurt (secretory protein in upper respiratory tracts) that was significantly induced by all-trans-retinoic acid in primary cultured human tracheobroncheal epithelia. Two alternatively spliced spurt transcripts of 1090 and 1035 base pairs exist that contain the same open reading frame expressing a 256-amino acid peptide. The full-length spurt cDNA sequence spans a genomic DNA fragment of 7,313 bp, and the gene is located on chromosome 20q11.21. spurt mRNA is notably expressed at high levels in human nasal, tracheal, and lung tissues. In situ hybridization demonstrated that spurt message is often present in secretory cell types. The human spurt gene product is a secretory protein that contains a distinct signal peptide sequence in its first 19 amino acids. Mono-specific antibodies were generated to characterize spurt expression. Our data demonstrate that spurt is secreted onto the apical side of primary human airway epithelial cultures and is present in clinical sputum samples. spurt gene expression is higher in sputum and tissue samples obtained from patients with chronic obstructive lung disease. Our results provide the cloning and characterization of this tissue-specific novel gene and its possible relationship with airway diseases.

Topics: Amino Acid Sequence; Cloning, Molecular; DNA, Complementary; Gene Expression Profiling; Genes; Humans; Lung Diseases, Obstructive; Molecular Sequence Data; Phosphorylation; Respiratory System; RNA, Messenger; Tretinoin

The metabolic activity of cytochrome P-450 enzymes has been associated with an increased risk of developing lung cancer. We found previously that all-trans retinoic acid is catabolized by these oxidative enzymes, and that an inhibitor of this system discriminated between two populations of lung cancer patients. We examined the association between this metabolic phenotype and the risk of lung cancer in 85 subjects. The area under the plasma concentration x time curve (AUC) was calculated after a single oral dose of all-trans retinoic acid (45 mg/m2). The mean AUC for patients who had either squamous or large cell carcinomas was significantly lower than that of patients with adenocarcinomas (P = 0.0001) or control subjects (P = 0.01). Individuals with an AUC < 250 ng x h/ml had a greater likelihood of having squamous or large cell carcinoma (odds ratio = 5.93). This study suggests that the "rapid" catabolism of all-trans retinoic acid is linked to an increased risk of squamous or large cell cancers of the lung.

Topics: Adenocarcinoma; Analysis of Variance; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Case-Control Studies; Disease Susceptibility; Female; Humans; Keratolytic Agents; Lung Diseases, Obstructive; Lung Neoplasms; Male; Middle Aged; Odds Ratio; Phenotype; Smoking; Tretinoin