epidermal-growth-factor and Metaplasia

Barrett's esophagus is an acquired metaplastic change that occurs in the distal esophagus secondary to chronic gastroesophageal reflux. This premalignant condition forms the most important risk factor for developing esophageal adenocarcinoma, which is an extremely aggressive tumor with a 5-year survival rate of less than 25%. Carcinomas that arise in the setting of Barrett's esophagus are thought to develop as part of the metaplasia-dysplasia-carcinoma sequence.. To review the current knowledge on the genomic alterations involved in the development of Barrett's esophagus and its progression to dysplasia and/or cancer.. Several changes in gene structure, gene expression, and protein structure are associated with the progression of Barrett's esophagus to adenocarcinoma. Accumulation of these changes seems to be essential, rather than the exact sequence of these changes. Multiple molecular pathways are involved and interact with each other. Alterations in tumor suppressor genes, amongst which p53 and p16, are early events in the metaplasia-dysplasia-adenocarcinoma sequence, followed by loss of cell cycle checkpoints. Ongoing genomic instability leads to cumulative genetic errors and thereby the generation of multiple clones of transformed cells.. Within the multistep process of esophageal adenocarcinogenesis, to date no single molecular marker came forward able to predict who will and who will not develop cancer in the setting of Barrett's esophagus. Instead, panels of markers need to be developed in the future allowing to indicate disease progression. Identification of crucial molecular pathways involved in esophageal adenocarcinogenesis would ultimately improve therapy and facilitate development of new treatment strategies.

Topics: Adenocarcinoma; Apoptosis; Barrett Esophagus; Chromosome Aberrations; Cyclin D1; DNA, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Esophageal Neoplasms; Gastroesophageal Reflux; Gene Expression Regulation, Neoplastic; Humans; Metaplasia; Microsatellite Repeats; Precancerous Conditions; Receptor, ErbB-2; Tumor Suppressor Protein p53

Topics: Cell Division; Conjunctiva; Dry Eye Syndromes; Epidermal Growth Factor; Epithelial Cells; Epithelium; Humans; Inflammation; Lacrimal Apparatus; Metaplasia; Models, Biological; Surface Properties; Tears; Transforming Growth Factor beta

To review genetic alterations in precancerous lesions and adenocarcinoma of the stomach.. Telomere reduction, tpr-met oncogenic rearrangement, overexpression of cripto, p53 mutations, adenomatous polyposis coli gene mutations and K-ras mutations, which are frequently associated with the well differentiated or intestinal type of stomach cancer, were found in intestinal metaplasia and adenoma of the stomach.. Among these genetic alterations, reduction of telomere repeat arrays might be the initial step in the genetic instability of stomach carcinogenesis. Some of the well differentiated type stomach cancers may develop by an accumulation of multiple gene changes similar to those of colorectal cancer.

Topics: Base Sequence; Biomarkers, Tumor; Epidermal Growth Factor; Gene Expression; Genes, Tumor Suppressor; GPI-Linked Proteins; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Intestines; Membrane Glycoproteins; Metaplasia; Molecular Sequence Data; Neoplasm Proteins; Oncogenes; Precancerous Conditions; Stomach Neoplasms; Telomere

Helicobacter heilmannii is a zoonotic bacterium that has been associated with gastric disease in humans. In this study, the mRNA expression of mucins in the stomach of BALB/c mice was analyzed at several time points during a 1-year infection with this bacterium, during which gastric disease progressed in severity. Markers for acid production by parietal cells and mucous metaplasia were also examined. In the first 9 weeks postinfection, the mRNA expression of Muc6 was clearly upregulated in both the antrum and fundus of the stomach of H. heilmannii-infected mice. Interestingly, Muc13 was upregulated already at 1 day postinfection in the fundus of the stomach. Its expression level remained high in the stomach over the course of the infection. This mucin is, however, not expressed in a healthy stomach, and high expression of this mucin has so far only been described in gastric cancer. In the later stages of infection, mRNA expression of H(+)/K(+)-ATPase α/β and KCNQ1 decreased, whereas the expression of Muc4, Tff2, Dmbt1, and polymeric immunoglobulin receptor (pIgR) increased starting at 16 weeks postinfection onwards, suggesting the existence of spasmolytic polypeptide-expressing metaplasia in the fundus of the stomach. Mucous metaplasia present in the mucosa surrounding low-grade mucosa-associated lymphoid tissue (MALT) lymphoma-like lesions was also histologically confirmed. Our findings indicate that H. heilmannii infection causes severe gastric pathologies and alterations in the expression pattern of gastric mucins, such as Muc6 and Muc13, as well as disrupting gastric homeostasis by inducing the loss of parietal cells, resulting in the development of mucous metaplasia.

Topics: Animals; Antigens, Surface; Disease Models, Animal; Epidermal Growth Factor; Female; Gastric Mucosa; Gene Expression Profiling; Helicobacter heilmannii; Helicobacter Infections; Intercellular Signaling Peptides and Proteins; Metaplasia; Mice; Mice, Inbred BALB C; Peptides; Trefoil Factor-2

Epidemiologic studies suggest that increased concentrations of airborne spores of Aspergillus fumigatus closely relate to asthma aggravation. Chronic exposure to A. fumigatus aggravates airway inflammation, remodeling, and airway hyperresponsiveness in asthmatic rats. The effects of chronic exposure to A. fumigatus on epidermal growth factor receptor (EGFR) expression in the airway epithelial cells of asthmatic rats remain unclear. This study aimed to investigate the effects of chronic exposure to A. fumigatus on injury and shedding of airway epithelium, goblet cell metaplasia, and EGFR expression in the airway epithelial cells of asthmatic rats. A rat model of chronic asthma was established using ovalbumin (OVA) sensitization and challenge. Rats with chronic asthma were then exposed to long-term inhalation of spores of A. fumigatus, and the dynamic changes in injury and shedding of airway epithelium, goblet cell metaplasia, and EGFR expression were observed and analyzed. Chronic exposure to A. fumigatus could aggravate airway epithelial cell damage, upregulate the expression of EGFR and its ligands EGF and TGF-α, promote goblet cell metaplasia, and increase airway responsiveness in rats with asthma. Chronic exposure to A. fumigatus upregulates the expression of EGFR and its ligands in asthmatic rats. The EGFR pathway may play a role in asthma aggravation induced by exposure to A. fumigatus.

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Epidermal Growth Factor; Epithelial Cells; ErbB Receptors; Goblet Cells; Male; Metaplasia; Ovalbumin; Pneumonia; Rats; Rats, Wistar

Gastric secretion can provide valuable information especially when Helicobacter pylori (Hp) infection results in chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) preceding adenocarcinoma (AdCa).. Looking for a potential biomarker of malignant transformation in the setting of chronic inflammation we studied the levels of prostaglandin E2 (PGE(2)), as well as peptide growth factors [epidermal growth factor (EGF) and transforming growth factor α (TGFα)], harbingers of injury and repair, in gastric juice aspirated at endoscopy from patients with CAG, CAG/IM, AdCa, and controls.. The PGE(2), EGF and TGFα concentrations in the gastric juice were measured using radioimmunoassays (RIAs).. In patients with AdCa gastric juice PGE(2) increased fivefold versus controls (P < 0.01) and almost threefold versus patients with CAG (P < 0.05). The EGF levels in patients with AdCa were fourfold higher versus controls (P < 0.001) and almost threefold higher versus CAG (P < 0.05). In patients with CAG/IM the EGF levels were also almost 3 times higher versus controls. The TGFα levels in patients with AdCa were half the value of controls and CAG (P < 0.05). In patients with CAG/IM the levels were as low as 1/5 of controls or CAG (P < 0.05).. Testing the gastric juice for PGE(2), EGF, and TGFα in patients with endoscopy and biopsy proven CAG, may be helpful in follow up of patients who may potentially progress to IM and ultimately AdCa. This could be considered as an adjunct to histologic assessment especially that even the best surveillance biopsy specimen regimens are inherited with sampling errors.

Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Digestive System Neoplasms; Dinoprostone; Epidermal Growth Factor; Female; Gastric Juice; Gastritis, Atrophic; Helicobacter Infections; Humans; Intestines; Male; Metaplasia; Middle Aged; Pilot Projects; Transforming Growth Factor alpha

To compare tear epidermal growth factor (EGF) concentration in dry eye (DE) conditions and determine correlations between EGF levels and severity of symptoms and ocular surface signs.. In this prospective case-control study, 35 patients with DE, including subgroups with meibomian gland disease (MGD), Sjögren's syndrome (SS) aqueous tear deficiency, or neurotrophic keratopathy (NK), and 17 asymptomatic control subjects were evaluated. Symptoms, Schirmer test, fluorescein clearance test (FCT), EGF concentration, dye staining, and the presence of corneal subepithelial fibrosis and meibomian gland (MG) orifice metaplasia were recorded. Tear EGF and the severity of irritation and ocular surface signs were correlated.. Tear EGF was higher in MGD than in the control (P = 0.03) and was lower in SS than in the control (P < 0.0001; MGD (P < 0.05) and NK (P < 0.01) groups. The DE subgroup with results in the FCT > 3 and Schirmer 1 >or= 8 had higher EGF levels than the group with FCT > 3 and Schirmer 1 < 8 and both groups with good tear clearance (P < 0.01). Tear EGF levels correlated inversely with conjunctival (r = -0.49, P = 0.0032) and corneal (r = -0.39, P = 0.022) dye staining and positively with MG orifice metaplasia (r = 0.36, P = 0.03) and corneal subepithelial fibrosis (r = 0.5, P = 0.0006).. Tear EGF concentration was increased in eyes with MGD, corneal subepithelial fibrosis, and MG orifice metaplasia. Elevated tear EGF may promote development of corneal subepithelial fibrosis and lid margin changes.

Topics: Case-Control Studies; Dry Eye Syndromes; Epidermal Growth Factor; Epithelium, Corneal; Eye Proteins; Eyelid Diseases; Female; Fibrosis; Fluorophotometry; Humans; Immunoassay; Male; Meibomian Glands; Metaplasia; Middle Aged; Prospective Studies; Tears

Mucus overproduction in inflammatory and obstructive airway diseases is associated with goblet cell (GC) metaplasia in airways. Although the mechanisms involved in GC metaplasia and mucus hypersecretion are not completely understood, association with oxidative stress and epidermal growth factor receptor (EGFR) signaling has been reported. To explore the mechanisms involved in oxidative stress-induced GC metaplasia, cultures of differentiated normal human bronchial epithelial cells grown at the air-liquid interface were exposed to reactive oxygen species (ROS) generated by xanthine/xanthine oxidase. EGFR activation and signaling was assessed by measuring EGF and transforming growth factor-alpha release and EGFR and (44/42)MAPK phosphorylation. The GC population was evaluated by confocal microscopy. ROS-induced EGFR activation resulted in GC proliferation and increased MUC5AC gene and protein expression. Signaling was due to pro-EGF processing by tissue kallikrein (TK), which was activated by ROS-induced hyaluronan breakdown. It was inhibited by catalase, a TK inhibitor, and EGF-blocking antibodies. Exposure to recombinant TK mimicked the ROS effects, increasing the expression of MUC5AC and lactoperoxidase. In addition, ROS induced the antiapoptotic factor Bcl-2 in a TK-dependent fashion. In conclusion, ROS-induced GC metaplasia in normal human bronchial epithelial cells is associated with HA depolymerization and EGF processing by TK followed by EGFR signaling, suggesting that increases in TK activity could contribute to GC metaplasia and mucus hypersecretion in diseases such as asthma and chronic bronchitis. The data also suggest that increases in GC population could be sustained by the associated upregulation of Bcl-2 in airway epithelial cells.

Topics: Cell Differentiation; Cell Proliferation; Epidermal Growth Factor; Epithelial Cells; ErbB Receptors; Goblet Cells; Humans; Hyaluronic Acid; Lactoperoxidase; Metaplasia; Mucin 5AC; Mucins; Oxidants; Oxidative Stress; Polymers; Protein Precursors; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Respiratory Mucosa; RNA, Messenger; Signal Transduction; Tissue Kallikreins; Xanthine Oxidase

The epidermal growth factor receptor (EGF-R) system plays a crucial role in mucus production in vitro and in rats. However, the role of the EGF-R system in humans is not known. We compared the localization of EGF-R and its ligands (epidermal growth factor and transforming growth factor alpha) in the epithelia of sinuses with chronic sinusitis and in those of healthy controls. Immunohistochemical techniques were employed to identify the presence of EGF-R and its ligands in the sinus mucosa. We found EGF-R in goblet cells, basal cells, and submucosal gland cells, but not in ciliated cells. Immunoreactivity for both epidermal growth factor and transforming growth factor alpha was found in the epithelial cells and inflammatory cells and in some submucosal gland cells. There was stronger staining of EGF-R and its ligand proteins in chronic sinusitis specimens than in controls. The interrelated localization of EGF-R and its ligands suggests a role in mucus production in the epithelium of the sinus mucosa.

Topics: Adult; Case-Control Studies; Chronic Disease; Epidermal Growth Factor; ErbB Receptors; Female; Goblet Cells; Humans; Hyperplasia; Immunohistochemistry; Ligands; Male; Maxillary Sinusitis; Metaplasia; Middle Aged; Mucus; Neutrophil Activation; Tomography, X-Ray Computed; Transforming Growth Factor alpha; Tumor Necrosis Factor-alpha

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is expressed in both normal pancreatic islets and in pancreatic cancers, but its role in pancreatic physiology and disease is not known. This report examines the effects of HB-EGF overexpression in mouse pancreas.. Transgenic mice were established using a tissue-specific promoter to express an HB-EGF complementary DNA in pancreatic beta cells, effectively elevating HB-EGF protein 3-fold over endogenous levels.. Mice overexpressing HB-EGF in pancreatic islets showed both endocrine and exocrine pancreatic defects. Initially, islets from transgenic mice failed to segregate alpha, beta, delta, and PP cells appropriately within islets, and had impaired separation from ducts and acini. Increased stroma was detected within transgenic islets, expanding with age to cause fibrosis of both endocrine and exocrine compartments. In addition to these structural abnormalities, subsets of transgenic mice developed profound hyperglycemia and/or proliferation of metaplastic ductal epithelium. Both conditions were associated with severe stromal expansion, suggesting a role for islet/stromal interaction in the onset of the pancreatic disease initiated by HB-EGF. Supporting this conclusion, primary mouse fibroblasts adhered to transgenic islets when the 2 tissues were cocultured in vitro, but did not interact with nontransgenic islets.. An elevation in HB-EGF protein in pancreatic islets led to altered interactions among islet cells and among islets, stromal tissues, and ductal epithelium. Many of the observed phenotypes appeared to involve altered cell adhesion. These data support a role for islet factors in the development of both endocrine and exocrine disease.

Topics: Animals; Cell Communication; Cell Division; Epidermal Growth Factor; Epithelial Cells; Fibroblasts; Fibrosis; Gene Expression; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Islets of Langerhans; Metaplasia; Mice; Mice, Transgenic; Pancreatic Diseases; Pancreatic Ducts; Phenotype

Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined.. The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice.. INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor alpha. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (< or = 8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P < or = 0.05).. These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.

Topics: Animals; Cell Count; Epidermal Growth Factor; Epithelial Cells; Gastric Acid; Gastrins; Gastritis, Atrophic; Helicobacter Infections; Heparin; Heparin-binding EGF-like Growth Factor; Hyperplasia; Hypertrophy; Intercellular Signaling Peptides and Proteins; Metaplasia; Mice; Mice, Transgenic; Stomach Neoplasms; Transforming Growth Factor alpha

Pancreatic acinar metaplasia of the gastric mucosa is a newly recognized entity. Its physiological relevance and association with other pathological conditions in the stomach remain to be elucidated. We studied by immunohistochemistry the expression of growth markers in the gastric mucosa in biopsies from 15 patients with recognized pancreatic metaplasia. Pancreatic metaplasia (both acinar and dispersed forms) was found in routine paraffin sections and confirmed by strong lipase immunoreactivity. In parallel paraffin sections we performed immunostaining for epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha) and epidermal growth factor receptor (EGFr) using a biotin streptavidin method. Strong expression of TGF alpha but only weak expression of EGF was noted within metaplastic mucosa. EGFr was strongly expressed, not only in areas of pancreatic metaplasia but also in the surrounding gastric mucosa.

Topics: Antibodies; Epidermal Growth Factor; Female; Gastric Mucosa; Gastritis, Atrophic; Humans; Lipase; Male; Metaplasia; Pancreas; Stomach; Transforming Growth Factor alpha

Almost all atypical epithelial lesions of the stomach consist of atypical cells in the superficial part of the glands and nonatypical cells in the deeper portion of the glands. A transition zone was formed between the superficial atypical gland cells and the deeper nonatypical gland cells. Positive cells were widely demonstrated with immunohistochemical stains for PCNA in the superficial atypical glands and transition zone. The rate of PCNA positivity was 37.7%. However, a small number of positive cells for EGFR (8.5%), c-erbB-2(11.3%), p53(11.3%) and c-K-ras(1.7%) were found in ATP. The incidence of positivity for these factors was low compared with that for carcinomas. The percentages of positive cells for EGFR(1.5%) and c-erbB-2(4.5%) were very low in intestinal metaplasia.

Topics: Epidermal Growth Factor; Epithelium; ErbB Receptors; Humans; Immunohistochemistry; Metaplasia; Nuclear Proteins; Oncogenes; Proliferating Cell Nuclear Antigen; Stomach

From 1976 to 1991, 151 cases of small cell carcinoma of the lung were diagnosed by fiberoptic bronchoscopic biopsy at our institution. One hundred twenty-eight of 151 cases provided suitable material for the examination of the morphologic changes in the bronchial surface epithelium. Thirty-seven percent of the cases showed normal bronchial epithelium, 47% showed benign squamous metaplasia, 9% showed atypical squamous metaplasia, and 5% showed squamous cell carcinoma in situ. Immunohistochemical examination for bombesin and epidermal growth factor was performed on selected biopsy specimens. The biopsy specimens chosen for immunohistochemistry included 20 specimens that showed normal bronchial epithelium, 20 specimens with benign squamous metaplasia, 12 specimens with atypical squamous metaplasia, and seven specimens with squamous cell carcinoma in situ. All the specimens showed positive staining with anti-bombesin. With anti-epidermal growth factor 10% of biopsy specimens with normal epithelium showed positive staining. The positive reaction increased from 25% for biopsy specimens with benign squamous metaplasia to 58% for biopsy specimens with atypical squamous metaplasia and to 71% for biopsy specimens with carcinoma in situ. These findings suggest a connection between epidermal growth factor production by small cell carcinoma of the lung cells and changes in the bronchial surface epithelium.

Topics: Biopsy; Bombesin; Bronchi; Carcinoma in Situ; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Epidermal Growth Factor; Epithelial Cells; Epithelium; Humans; Immunohistochemistry; Lung Neoplasms; Metaplasia

The concentration of insulin-like growth factor-I (IGF-I) and its relationship to other biochemical parameters of cyst fluids was investigated in 94 cyst fluids of 86 women with gross cystic breast disease. The relationship between the biochemical parameters and the cytological features of breast fluids (presence or absence of apocrine cells) was also studied. IGF-I was detected in all tested fluids, with a concentration 50 to 100 times lower than that found in plasma. IGF-I concentration was higher in cysts with a Na+/K+ ratio greater than 3 (greater than 3) and was inversely related to both dehydroepiandrosterone sulfate (DHEA-S) and epidermal growth factor (EGF) concentration (p less than 0.001). It is suggested that Na+/K+ greater than 3 cysts have a higher permeability to plasma and extracellular fluids compared to Na+/K+ less than 3 cysts. Apocrine cells were found in 78% of Na+/K+ less than 3 fluids as well as in 53% of Na+/K+ greater than 3 fluids. A well-defined relationship was found between the biochemical parameters of breast fluids, but the presence of either IGF-I or EGF was not related to the morphology of breast cysts as assessed by cytological examination.

Topics: Biopsy, Needle; Body Fluids; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Epidermal Growth Factor; Epithelium; Female; Fibrocystic Breast Disease; Humans; Insulin-Like Growth Factor I; Metaplasia; Potassium; Precancerous Conditions; Sodium

Epidermal growth factor, and its human homologue urogastrone (EGF/URO), are secreted by the gut-associated salivary and Brunner's glands. Recombinant EGF/URO is a powerful stimulator of cell proliferation and differentiation in the rodent and neonatal human intestine. But EGF/URO is not absorbed from the adult gut and has no action when given through the gut lumen; thus the role of secreted EGF/URO is unknown. We now report that ulceration of the epithelium anywhere in the human gastrointestinal tract induces the development of a novel cell lineage from gastrointestinal stem cells. This lineage initially appears as a bud from the base of intestinal crypts, adjacent to the ulcer, and grows locally as a tubule, ramifying to form a new small gland, and ultimately emerges onto the mucosal surface. The lineage produces neutral mucin, shows a unique lectin-binding profile and immunophenotype, is nonproliferative, and contains and secretes abundant immunoreactive EGF/URO. We propose that all gastrointestinal stem cells can produce this cell lineage after mucosal ulceration, secreting EGF/URO to stimulate cell proliferation, regeneration and ulcer healing. This cell lineage is very commonly associated with gastrointestinal mucosal ulceration, and we conclude that a principal in vivo role for EGF/URO is to stimulate ulcer healing throughout the gut through induction of this cell lineage in the adjacent mucosa.

Topics: Crohn Disease; Epidermal Growth Factor; Histocytochemistry; Humans; Intestinal Mucosa; Metaplasia; Mucins; Peptic Ulcer

Twelve pairs of fetal lambs were used to test the hypothesis that the necrotizing tracheobronchitis followed by squamous metaplasia seen in premature infants who develop chronic bronchopulmonary dysplasia might be related to low retinol stores and might, therefore, be reversed by retinol supplementation. Epidermal growth factor (EGF) was used to model the growth factor stimulus initiated by chronic wounding of the airways, and retinol was used as a differentiator of proliferating cells stimulated by EGF. Saline-treated animals were used as controls, as were fetal lambs receiving retinol alone or EGF alone. The effects of EGF on tracheal and bronchial epithelium consisted of proliferation of basal and intermediate cells, necrosis and slough of lining ciliated and mucous-producing cells, followed by squamous metaplasia. In fetal lambs given retinol, plasma, liver and lung retinol levels rose and mucous producing cells were increased in number. In the presence of EGF plus retinol, differentiation of mucous-producing cells was accelerated. We believe that this fetal lamb model with low initial levels of retinol in plasma, liver and lung, treated with EGF may mimic human premature infants with chronic bronchopulmonary dysplasia, and that the addition of retinol in amounts sufficient to raise their tissue levels produces a more normal surface epithelium in conducting airways.

Topics: Analysis of Variance; Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Cell Differentiation; Cell Division; Disease Models, Animal; Epidermal Growth Factor; Epithelium; Female; Fetus; Humans; Infant, Newborn; Metaplasia; Microscopy, Electron; Pregnancy; Sheep; Trachea; Vitamin A; Vitamin A Deficiency