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Biomedical subjects

M T Stahlman

Publications and source records attributed to M T Stahlman.

At least 19 recordsLinked to original sources
PubMed2001

TGF-beta1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo.

Members of the transforming growth factor beta (TGF-beta) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-beta signaling in lung morphogenesis, a constitutively active form of TGF-beta1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-beta1 arrested lung morphogenesis in the pseudoglandular stage of development, inhibiting synthesis of differentiation-dependent proteins, SP-B, SP-C, and CCSP, and maintaining embryonic patterns of staining for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor-3beta (HNF-3beta). The pulmonary mesenchyme was thickened and vascular density was increased by TGF-beta1. TGF-beta1 decreased expression of vascular endothelial growth factor-A (VEGF-A) mRNA and protein, and the abundance of Flk-1 mRNA in the lung mesenchyme. Distribution of platelet-endothelial cell adhesion molecule (PECAM)-1, a marker of pulmonary blood vessels, was altered, and ultrastructural studies demonstrated that TGF-beta1 inhibited vascular development in the fetal lung. TGF-beta1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF-beta receptor pathway is critical for normal lung morphogenesis.

Animals↗
PubMed2001

FGF-10 disrupts lung morphogenesis and causes pulmonary adenomas in vivo.

Transgenic mice in which fibroblast growth factor (FGF)-10 was expressed in the lungs of fetal and postnatal mice were generated with a doxycycline-inducible system controlled by surfactant protein (SP) C or Clara cell secretory protein (CCSP) promoter elements. Expression of FGF-10 mRNA in the fetal lung caused adenomatous malformations, perturbed branching morphogenesis, and caused respiratory failure at birth. When expressed after birth, FGF-10 caused multifocal pulmonary tumors. FGF-10-induced tumors were highly differentiated papillary and lepidic pulmonary adenomas. Epithelial cells lining the tumors stained intensely for thyroid transcription factor (TTF)-1 and SP-C but not CCSP, indicating that FGF-10 enhanced differentiation of cells to a peripheral alveolar type II cell phenotype. Withdrawal from doxycycline caused rapid regression of the tumors associated with rapid loss of the differentiation markers TTF-1, SP-B, and proSP-C. FGF-10 disrupted lung morphogenesis and induced multifocal pulmonary tumors in vivo and caused reversible type II cell differentiation of the respiratory epithelium.

Adenoma↗
PubMed2000

Lamellar body formation in normal and surfactant protein B-deficient fetal mice.

Surfactant protein B (SP-B) -/- mice die of lethal respiratory distress syndrome shortly after birth. Alveolar type II epithelial cells in SP-B-deficient mice are characterized by a complete absence of lamellar bodies, the intracellular storage form of pulmonary surfactant, and the presence of inclusions containing numerous small vesicles and electron-dense masses. The present study was undertaken to characterize the formation of these inclusions during fetal lung development and clarify their relationship to lamellar bodies. In wild-type and SP-B +/- mice, small lamellar bodies with loosely organized lamellae and distinct limiting membranes were first detected on day 16 to 16.5 of gestation. SP-B -/- mice were readily identified on day 16 by the absence of immature lamellar bodies, the appearance of vesicular inclusions similar to those previously described in late gestation SP-B -/- mice, and the accumulation of misprocessed SP-C protein. Vesicular inclusions were rarely detected in SP-B +/- mice and were never detected in wild-type littermates. Classical multivesicular bodies were observed fusing with lamellar bodies in wild-type mice, and with the vesicular inclusions in SP-B -/- mice that occasionally contained a few membrane lamellae. On day 18, the airways of SP-B -/- mice lacked tubular myelin and were filled with vesicles and electron-dense masses, suggesting that the contents of the vesicular inclusions were secreted. Taken together, these observations suggest that vesicular inclusions in SP-B -/- mice are disorganized lamellar bodies in which the absence of SP-B leads to failure to package surfactant phospholipids into concentric lamellae.

Animals↗
PubMed1999

Utility of surfactant protein B precursor and thyroid transcription factor 1 in differentiating adenocarcinoma of the lung from malignant mesothelioma.

Differentiation of malignant mesothelioma from adenocarcinoma, particularly from a lung primary, remains a difficult diagnostic problem. Surfactant protein B precursor (pro-SP-B) and thyroid transcription factor 1 (ITF-1) are expressed selectively in the normal respiratory epithelium and in adenocarcinomas of the lung. In this study, we evaluated the utility of pro-SP-B and ITF-1 in distinguishing pulmonary adenocarcinomas and malignant mesotheliomas. Immunoreactivity for pro-SP-B and TTF-1 was examined in paraffin sections of 370 primary lung carcinomas (208 adenocarcinomas, 101 squamous cell carcinomas, and 61 large cell carcinomas) and 95 malignant mesotheliomas, using a pro-SP-B antiserum and a monoclonal TTF-1 antibody with a biotin-streptavidin detection system. Immunostaining for pro-SP-B was detected in 57% of adenocarcinomas, and 20% of large cell carcinomas. Immunoreactivity for TTF-1 was shown in 76% of adenocarcinomas and 26% of large cell carcinomas. Malignant mesotheliomas and squamous cell carcinomas did not stain with either antibody. The expression of pro-SP-B and TTF-1 in adenocarcinomas of the lung but not in malignant mesotheliomas shows that pro-SP-B and TTF-1 staining is useful in differentiating these neoplasms.

Adenocarcinoma↗
PubMed1998

Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo.

Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of collagenous lectin domain-containing proteins that is expressed in epithelial cells of the lung. The SP-D gene was targeted by homologous recombination in embryonic stem cells that were used to produce SP-D (+/-) and SP-D (-/-) mice. Both SP-D (-/-) and SP-D (+/-) mice survived normally in the perinatal and postnatal periods. Whereas no abnormalities were observed in SP-D (+/-) mice, alveolar and tissue phosphatidylcholine pool sizes were markedly increased in SP-D (-/-) mice. Increased numbers of large foamy alveolar macrophages and enlarged alveoli were also observed in SP-D (-/-) mice. Phospholipid composition was unaltered in SP-D (-/-) mice, but surfactant morphology was abnormal, consisting of dense phospholipid membranous arrays with decreased tubular myelin. The pulmonary lipoidosis in the SP-D (-/-) mice was not associated with accumulation of surfactant proteins B or C, or their mRNAs, distinguishing the disorder from alveolar proteinosis syndromes. Surfactant protein A mRNA was reduced and, SP-A protein appeared to be reduced in SP-D (-/-) compared with wild type mice. Targeting of the mouse SP-D gene caused accumulation of surfactant lipid and altered phospholipid structures, demonstrating a previously unsuspected role for SP-D in surfactant lipid homeostasis in vivo.

Animals↗
PubMed1998

Temporal-spatial distribution of hepatocyte nuclear factor-3beta in developing human lung and other foregut derivatives.

We assessed the temporal-spatial distribution of hepatocyte nuclear factor-3beta (HNF-3beta) in developing human lung and other foregut derivatives. Tissue from 31 fetuses (10-40 weeks) and 24 infants with hyaline membrane disease (HMD) or bronchopulmonary dysplasia (BPD) (2 days to 7 months) was studied. HNF-3beta was detected in nuclei of epithelial cells of trachea and of conducting and terminal airways at 10 weeks. Thereafter, epithelial nuclei were immunolabeled more widely in peripheral than proximal airways. HNF-3beta was confined to bronchiolo-alveolar portals and Type II cells in nonfetal lung. In infants with BPD, HNF-3beta was expressed abundantly in regenerating epithelial cells at the periphery of lung lobules. HNF-3beta was also detected in fetal esophagus, pancreas, duodenum, stomach, and gallbladder, suggesting that it is a marker for progenitor cells in foregut derivatives. The pattern of expression of HNF-3beta in the lung was similar to that of thyroid transcription factor-1 (TTF-1) at all ages. The temporal-spatial patterns of HNF-3beta and TTF-1 in the developing and regenerating lung are consistent with their proposed role in epithelial cell differentiation, regeneration, and surfactant protein gene expression. (J Histochem Cytochem 46:955-962, 1998)

Bronchi↗
PubMed1997

Immunogold EM localization of neurochemicals in human pulmonary neuroendocrine cells.

Antibodies against the pulmonary neuroendocrine cell peptides gastrin-releasing peptide (bombesin), calcitonin and calcitonin gene-related peptide (CGRP) have been labeled with colloidal gold spheres for immunocytochemical localization in human fetal and newborn lung tissue. In general, the presence and amount of immunolabeling increased with increasing gestational age, with only calcitonin appearing late in fetal life. The largest percentage of neuroepithelial body (NEB) cells labeled and the largest number of labeled dense core vesicles (DCV) were in infants with chronic lung disease (bronchopulmonary dysplasia). Serial ribbons allowed identification of more than one peptide in a single NEB cell. The use of two antibodies labeled with colloidal gold spheres of different sizes allowed the identification of two peptides in the same DCV. Quantification of relative amounts of labeled peptides was not possible, as the peptide labeling with the larger size gold sphere was consistently underestimated. Colocalization to the same DCV has been shown in humans for bombesin and calcitonin, calcitonin and CGRP, bombesin and CGRP and, by others for cholecystokinin (CCK) and serotonin. Colocalization of two or more peptides or an amine to a single DCV within the same cell implies simultaneous discharge by exocytosis. The action of the two (or more) substances might be in concert, perhaps with one acting in a paracrine fashion, and the second in an autocrine fashion. In this case, the second peptide or amine might have a regulatory function in the parent cell, influencing DCV storage or rate of release.

Bombesin↗
PubMed1997

Expression of surfactant protein B precursor and surfactant protein B mRNA in adenocarcinoma of the lung.

Surfactant protein B (SP-B) is a 79-amino acid, hydrophobic protein that plays important roles in surfactant function and homeostasis. SP-B is produced in the respiratory epithelium by proteolytic processing of a glycosylated precursor (pro-SP-B) of relative molecular mass 42,000 to 46,000. To develop diagnostic markers for pulmonary adenocarcinomas, we examined the incidence and distribution of pro-SP-B and SP-B mRNA in paraffin sections of 35 non-small cell lung carcinomas (15 adenocarcinomas, 15 squamous cell carcinomas, and 5 large cell carcinomas), using immunohistochemical techniques and in situ hybridization. Fifteen nonpulmonary adenocarcinomas were used as controls. Pro-SP-B and SP-B mRNA were detected in 60% and 53% of pulmonary adenocarcinomas, respectively. Expression was seen in adenocarcinomas with acinar, papillary, bronchioloalveolar, and solid growth patterns. Squamous cell and large cell carcinomas of the lung and nonpulmonary adenocarcinomas did not contain pro-SP-B immunoreactivity or SP-B mRNA. The specificity of SP-B gene expression in adenocarcinomas of the lung supports the usefulness of pro-SP-B and SP-B mRNA in the study and diagnosis of these neoplasms.

Adenocarcinoma↗
PubMed1996

Ontogeny of Clara cell-specific protein and its mRNA: their association with neuroepithelial bodies in human fetal lung and in bronchopulmonary dysplasia.

Clara cell-specific 10-KD protein (CCSP) is an abundant product of nonciliated bronchiolar epithelial (Clara) cells in the lung. We have determined the temporal-spatial distribution of CCSP and its mRNA in developing human lung and in neonatal lung disease, using immunohistochemistry and in situ hybridization. CCSP immunoreactivity was found in nonciliated bronchiolar epithelial cells from 12 weeks of gestation onward. Tracheal and bronchial epithelia showed positive immunoreactivity at each gestational week after 15 weeks and 14 weeks, respectively. CCSP mRNA was seen in the bronchial and bronchiolar epithelia from 16 weeks onward and was detected in the trachea from 19 through 23 weeks of gestation. CCSP immunoreactivity and mRNA were present in nonciliated single cells of bronchial and bronchiolar epithelia in fetuses and in infants with and without lung disease. CCSP- and CCSP mRNA-containing epithelial cells also formed dusters around neuroepithelial bodies (NEBs), especially at airway branch points, suggesting that NEBs and Clara cells might interact during development and during pulmonary regeneration. Because of evidence of overlapping of some but not all cells expressing CCSP, SP-A, and pro-SP-B during lung development, a common cell lineage is proposed, with subsequent divergence of phenotypes.

Bronchopulmonary Dysplasia↗
PubMed1996

Expression of thyroid transcription factor-1(TTF-1) in fetal and neonatal human lung.

We assessed the immunohistochemical localization of thyroid transcription factor-1 (TTF-1) in the lungs of 24 human fetuses (11-23 weeks), three infants without pulmonary pathology (36-42 weeks), and 24 infants (2 days-6.5 months) with hyaline membrane disease (HMD) or bronchopulmonary dysplasia (BPD). TTF-1 was detected in fetal lung epithelial cell nuclei by 11 weeks' gestation. Budding tips of terminal airways had prominently labeled nuclei. By 17 weeks, labeling was present in scattered nonciliated columnar and cuboidal cells. Throughout gestation, TTF-1 nuclear staining was prominent in airways abutting pleural, peribronchial, or perivascular connective tissue, being less prominent in centers of lobules. By 23 weeks, many cells in cuboidal but not columnar cell-lined airways had labeled nuclei. At term, TTF-1 was detected primarily in Type II epithelial cells. In HMD with alveolar hemorrhage, edema, or airway collapse, little or no TTF-1 was present except in open terminal airways. In BDP lungs, TTF-1 was absent in areas of alveolar collapse or infection, being present in regenerating open airways. The temporal-spatial distribution of TTF-1, in general, follows patterns of distribution of surfactant protein-B in developing and pathological lungs, consistent with its role in the regulation of epithelial cell gene expression in the lung.

Bronchopulmonary Dysplasia↗
PubMed1995

Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.

Surfactant protein B (SP-B) is an 8.7-kDa, hydrophobic protein that enhances the spreading and stability of surfactant phospholipids in the alveolus. To further assess the role of SP-B in lung function, the SP-B gene was disrupted by homologous recombination in murine mouse embryonic stem cells. Mice with a single mutated SP-B allele (+/-) were unaffected, whereas homozygous SP-B -/- offspring died of respiratory failure immediately after birth. Lungs of SP-B -/- mice developed normally but remained atelectatic in spite of postnatal respiratory efforts. SP-B protein and mRNA were undetectable and tubular myelin figures were lacking in SP-B -/- mice. Type II cells of SP-B -/- mice contained no fully formed lamellar bodies. While the abundance of SP-A and SP-C mRNAs was not altered, an aberrant form of pro-SP-C, 8.5 kDa, was detected, and fully processed SP-C peptide was markedly decreased in lung homogenates of SP-B -/- mice. Ablation of the SP-B gene disrupts the routing, storage, and function of surfactant phospholipids and proteins, causing respiratory failure at birth.

Animals↗
PubMed1995

Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.

The human gene encoding thyroid transcription factor-1 (TTF-1), a homeodomain-containing nuclear transcription protein of the Nkx2 gene family, was isolated and characterized. Human TTF-1 was encoded by a single gene locus spanning approximately 3.3 kilobases and consisted of two exons and a single intron. The TTF-1 cDNA and polypeptide of 371 amino acids have been highly conserved, sharing 98% identity with the rat TTF-1 polypeptide. Human TTF-1 mRNA and polypeptide were selectively expressed in human and mouse pulmonary adenocarcinoma cell lines. In addition to its presence in thyroid gland epithelium, the human TTF-1 protein was detected by immunohistochemistry in human fetal lung as early as 11 weeks of gestation, being localized in the nuclei of epithelial cells of the developing airways. After birth, TTF-1 was selectively expressed in Type II epithelial cells in the alveoli and in subsets of bronchiolar epithelial cells in the conducting regions of the lung. The 5'-flanking region of the human TTF-1 gene directed transcription of luciferase cDNA in a lung epithelial cell-selective manner. The conservation and distribution of TTF-1 in the human respiratory tract support its role in the regulation of lung development and surfactant homeostasis.

Adult↗
PubMed1995

Vitamin A status and airway infection in mechanically ventilated very-low-birth-weight neonates.

Vitamin A (retinol) plays an important role in immunity. Respiratory and enteral infections in children are associated with low serum vitamin A concentrations that improve during recovery. To test the hypothesis that airway infection in very-low-birth-weight (VLBW) neonates likewise may be associated with a change in vitamin A status, we examined 20 VLBW neonates (selection criteria: birth weight 700-1300 g, gestational age 26-30 weeks, need for supplemental oxygen and mechanical ventilation for > 72 hr after birth) who were enrolled in the control group of a randomized clinical trial of vitamin A supplementation reported earlier. We studied changes in weekly measurements of plasma concentrations of vitamin A and retinol-binding protein (RBP) during 4 weeks following enrollment in the trial (postnatal day 4) and compared changes between periods with and without airway infections. Seventeen infants had 22 episodes of documented airway infection. Staphylococcus epidermidis was the predominant organism. Plasma vitamin A concentrations decreased during 19 out of 22. With airway infection (mean change: -4.1 to -18.6 micrograms/dL), while they increased during 37 out of 58 periods without airway infection (mean change: -0.2 to +5.8 micrograms/dl; P < 0.001). The mean (+/- SD) plasma vitamin A concentrations before, during, 1 week after, and 2 weeks after an episode of airway infection were 20.9 +/- 8.3, 9.7 +/- 4.1, 12.8 +/- 8.9, and 16.2 +/- 7.2 micrograms/dL, respectively. The mean value during airway infection was significantly lower than those before and two weeks after airway infection (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial Infections↗
PubMed1995

Safety and pharmacokinetics of vitamin A therapy for infants with respiratory syncytial virus infections.

Infants with respiratory syncytial virus infection have low serum vitamin A levels. We treated 21 respiratory syncytial virus-infected children with 12,500 to 25,000 IU of oral vitamin A. Vitamin A levels were normalized at 6 h, and none of the children experienced vitamin A toxicity or exacerbation of respiratory illness. Vitamin A treatment of previously healthy respiratory syncytial virus-infected infants at these doses is safe and well tolerated.

Humans↗
PubMed1994

Serum vitamin A levels in respiratory syncytial virus infection.

Respiratory syncytial virus causes worldwide epidemics of respiratory disease. Of 23 children infected with respiratory syncytial virus, 65% had low serum concentrations of vitamin A during acute illness; these low values were associated with more severe illness. Vitamin A supplementation may have a role in the management of infection with respiratory syncytial virus.

Case-Control Studies↗