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1.
Zhongguo Zhen Jiu ; 39(6): 632-6, 2019 Jun 12.
Artigo em Chinês | MEDLINE | ID: mdl-31190501

RESUMO

OBJECTIVE: To compare the effects of electroacupuncture (EA) at "Zusanli" (ST 36) versus "Yanglingquan" (GB 34) in the pregnant rats on perinatal nicotine-exposure-induced lung function and morphology of newborn rats and explore the rule of acupoint effect in EA for the prevention from lung dysplasia in newborn rats. METHODS: A total of 24 female SD rats were randomized into a normal saline group (S group), a nicotine group (N group), a nicotine-ST 36 group (N + ST 36 group) and a nicotine-GB 34 group (N+GB 34 group), 6 rats in each one. Starting at the 6th day of pregnancy, 0.9% sodium chloride solution was injected subcutaneously in the S group, 1 mg/kg; and in the rest 3 groups, nicotine of the same dose was injected through to the 21st postnatal day to establish the perinatal nicotine-exposure model. Simultaneously, during model preparation, EA was applied at "Zusanli" (ST 36) and "Yanglingquan" (GB 34) in the N+ST 36 group and the N+GB 34 group respectively, once a day, through to the 21st postnatal day. The lung function analytic system for small animal was adopted to observe the changes in lung function indicators in newborn rats, such as peak inspiratory flow (PIF), peak expiratory flow (PEF), expiratory resistance (RE), inspiratory resistance (RI) and dynamic compliance (Cdyn). HE staining was used to observe the morphological changes of lung, such as alveolar fusion and rupture. RESULTS: Compared with the S group, PEF and Cdyn were lower and PIF, RI and RE higher in the N group (all P<0.01), additionally, alveoli were fused and ruptured, alveolar wall thickened, the numbers of alveoli reduced, the interspace of alveoli enlarged and the diameter increased (P<0.01). Compared with the N group, in the N+ST 36 group, PEF and Cdyn were increased, PIF, RI and RE reduced (P<0.05, P<0.01), the alveolar fusion and rupture relieved, the numbers of alveoli increased, alveolar wall thinner, the interpsace of alveoli became normal and the diameter was reduced significantly (P<0.01). In the N+GB 34 group, the changes of lung function and morphological indicators were not significant (P>0.05). CONCLUSION: Electroacupuncture at "Zusanli" (ST 36) in the pregnant rats significantly improves the perinatal nicotine-exposure-induced lung function and morphology of newborn rats than electroacupuncture at "Yanglingquan" (GB 34).


Assuntos
Eletroacupuntura , Pulmão , Nicotina , Pontos de Acupuntura , Animais , Animais Recém-Nascidos , Feminino , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Nicotina/toxicidade , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
2.
J Perinatol ; 38(2): 164-168, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29072676

RESUMO

OBJECTIVE: Though nasal continuous positive airway pressure (NCPAP) is commonly used for non-invasive neonatal respiratory support, the optimal method of weaning NCPAP is not established. In this prospective, two-center randomized control trial we hypothesize that gradually increasing spontaneous breathing time off NCPAP increases successful weaning from NCPAP in infants born <31 weeks gestational age. STUDY DESIGN: Infants were randomized to one of the two NCPAP weaning protocols, a sprinting, that is, gradually increasing spontaneous breathing time off CPAP, protocol vs a non-sprinting (weaning pressure down) protocol. RESULT: Eighty-six infants were enrolled in one of the two study groups. Thirty-one infants (77%) in the sprinting group and 30 (75%) in the non-sprinting group were successfully weaned off NCPAP at the first attempt (P>0.05). It took 1.3 (1 to 1.75) (median (IQR)) attempts and 7 (7 to 7) days to wean NCPAP off in the sprinting group vs 1.3 (1 to 1.75) attempts and 7 (7 to 10) days in the non-sprinting group (P>0.05). Additionally, no differences in the secondary outcomes of bronchopulmonary dysplasia, severe retinopathy of prematurity (⩾stage 3), periventricular leukomalacia and length of stay were noted between the two groups. CONCLUSION: Weaning NCPAP via sprinting or non-sprinting protocol is comparable, not only for successful weaning but also for the occurrence of common neonatal morbidities that impact the long-term outcome in premature infants (ClinicalTrials.gov number, NCT02819050).

3.
Mol Genet Metab ; 114(4): 604-12, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25661292

RESUMO

Due to the active inhibition of the adipogenic programming, the default destiny of the developing lung mesenchyme is to acquire a myogenic phenotype. We have previously shown that perinatal nicotine exposure, by down-regulating PPARγ expression, accentuates this property, culminating in myogenic pulmonary phenotype, though the underlying mechanisms remained incompletely understood. We hypothesized that nicotine-induced PPARγ down-regulation is mediated by PPARγ promoter methylation, controlled by DNA methyltransferase 1 (DNMT1) and methyl CpG binding protein 2 (MeCP2), two known key regulators of DNA methylation. Using cultured alveolar interstitial fibroblasts and an in vivo perinatal nicotine exposure rat model, we found that PPARγ promoter methylation is strongly correlated with inhibition of PPARγ expression in the presence of nicotine. Methylation inhibitor 5-aza-2'-deoxycytidine restored the nicotine-induced down-regulation of PPARγ expression and the activation of its downstream myogenic marker fibronectin. With nicotine exposure, a specific region of PPARγ promoter was significantly enriched with antibodies against chromatin repressive markers H3K9me3 and H3K27me3, dose-dependently. Similar data were observed with antibodies against DNA methylation regulatory factors DNMT1 and MeCP2. The knock down of DNMT1 and MeCP2 abolished nicotine-mediated increases in DNMT1 and MeCP2 protein levels, and PPARγ promoter methylation, restoring nicotine-induced down regulation of PPARγ and upregulation of the myogenic protein, fibronectin. The nicotine-induced alterations in DNA methylation modulators DNMT1 and MeCP2, PPARγ promoter methylation, and its down-stream targets, were also validated in perinatally nicotine exposed rat lung tissue. These data provide novel mechanistic insights into nicotine-induced epigenetic silencing of PPARγ that could be exploited to design novel targeted molecular interventions against the smoke exposed lung injury in general and perinatal nicotine exposure induced lung damage in particular.


Assuntos
Epigênese Genética , Pulmão/citologia , Nicotina/toxicidade , PPAR gama/genética , Alvéolos Pulmonares/metabolismo , Animais , Azacitidina/análogos & derivados , Azacitidina/antagonistas & inibidores , Sequência de Bases , Células Cultivadas , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Decitabina , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Fibroblastos/metabolismo , Fibronectinas/genética , Humanos , Pulmão/ultraestrutura , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Dados de Sequência Molecular , Gravidez , Regiões Promotoras Genéticas , Alvéolos Pulmonares/citologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Fumar/efeitos adversos , Regulação para Cima
4.
J Neonatal Perinatal Med ; 7(3): 213-22, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25322997

RESUMO

OBJECTIVE: Evaluate plasma markers of myocardial function and ischemia [B-type natriuretic peptide] (BNP) and cardiac troponin T (cTnT)] in relationship to echocardiographic indices of left ventricular (LV) function and severity of illness score (SNAPPE-II) in Very-Low-Birth-Weight-Infants (VLBWIs) prospectively. STUDY DESIGN: Serial echocardiography studies, clinical data, BNP and cTnT were obtained in thirty VLBWIs on postnatal days 1, 2, 3 and 7. RESULTS: BNP increased and cTnT decreased significantly day 1 through 3. BNP was significantly associated with patent ductus arteriosus (PDA), but did not correlate with LV function or cTnT and did not reflect use of inotropic medication. Cardiac troponin T increased with severity of illness, SNAPPE-II, score and was highest in babies receiving inotropic medication; Low cardiac output (CO) was common in the first seventy two hours and correlated negatively with cTnT (p < 0.01). A contractility index, the corrected LV mean velocity of circumferential fiber shortening, (mVcfc) was not related to cTnT. The LV mVcfc was inversely related to LV end systolic wall stress (p < 0.001) in all subgroups, and this index of contractility (mvcfc-ess) did not differ with large caliber PDA or use of inotropic medication. CONCLUSION: Cardiac troponin T exclusively rather than a combined biomarker approach may be useful in assessing myocardial injury. Cardiac output was low in sick VLBWIs with myocardial ischemia. Left ventricular contractile state was apparently preserved in significantly ill babies with elevated cTnT. Further research is needed to define the complex relationship between biomarkers and echocardiographic indices.


Assuntos
Permeabilidade do Canal Arterial/diagnóstico por imagem , Doenças do Prematuro/diagnóstico por imagem , Recém-Nascido de muito Baixo Peso , Peptídeo Natriurético Encefálico/sangue , Troponina T/sangue , Disfunção Ventricular Esquerda/diagnóstico por imagem , Biomarcadores/sangue , Permeabilidade do Canal Arterial/sangue , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/sangue , Recém-Nascido de muito Baixo Peso/sangue , Recém-Nascido de muito Baixo Peso/fisiologia , Modelos Logísticos , Masculino , Índice de Gravidade de Doença , Método Simples-Cego , Ultrassonografia , Disfunção Ventricular Esquerda/sangue
5.
Am J Physiol Lung Cell Mol Physiol ; 305(4): L301-11, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23812632

RESUMO

Curcumin, a potent anti-inflammatory and antioxidant agent, modulates peroxisome proliferator-activated receptor-γ signaling, a key molecule in the etiology of bronchopulmonary dysplasia (BPD). We have previously shown curcumin's acute protection against neonatal hyperoxia-induced lung injury. However, its longer-term protection against BPD is not known. Hypothesizing that concurrent treatment with curcumin protects the developing lung against hyperoxia-induced lung injury long-term, we determined if curcumin protects against hyperoxic neonatal rat lung injury for the first 5 days of life, as determined at postnatal day (PND) 21. One-day-old rat pups were exposed to either 21 or 95% O2 for 5 days with or without curcumin treatment (5 mg/kg) administered intraperitoneally one time daily, following which the pups grew up to PND21 in room air. At PND21 lung development was determined, including gross and cellular structural and functional effects, and molecular mediators of inflammatory injury. To gain mechanistic insights, embryonic day 19 fetal rat lung fibroblasts were examined for markers of apoptosis and MAP kinase activation following in vitro exposure to hyperoxia for 24 h in the presence or absence of curcumin (5 µM). Curcumin effectively blocked hyperoxia-induced lung injury based on systematic analysis of markers for lung injury (apoptosis, Bcl-2/Bax, collagen III, fibronectin, vimentin, calponin, and elastin-related genes) and lung morphology (radial alveolar count and alveolar septal thickness). Mechanistically, curcumin prevented the hyperoxia-induced increases in cleaved caspase-3 and the phosphorylation of Erk1/2. Molecular effects of curcumin, both structural and cytoprotective, suggest that its actions against hyperoxia-induced lung injury are mediated via Erk1/2 activation and that it is a potential intervention against BPD.


Assuntos
Curcumina/uso terapêutico , Hiperóxia/tratamento farmacológico , Hiperóxia/prevenção & controle , Pulmão/embriologia , Pulmão/patologia , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Elastina/genética , Elastina/metabolismo , Ativação Enzimática/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibronectinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperóxia/embriologia , Hiperóxia/genética , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Mesoderma/patologia , Substâncias Protetoras/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/metabolismo , Triglicerídeos/metabolismo
6.
Am J Physiol Lung Cell Mol Physiol ; 297(3): L496-505, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19574420

RESUMO

Although alveolar wall thinning has been attributed to apoptosis of interstitial lung lipofibroblasts (LFs), the underlying molecular mechanism(s) remains unknown. Although the physiological vitamin D steroid hormone 1alpha,25(OH)(2)D(3) (1,25D) has been suggested as a local paracrine/autocrine effector of fetal lung maturation and is known to affect fibroblast apoptosis, its effects on LF apoptosis are unknown. We determined the role of 1,25D and its metabolite, C-3-epimer (3-epi-1,25D), on LF and alveolar type II (ATII) cell differentiation, proliferation, and apoptosis. Embryonic day 19 Sprague-Dawley fetal rat lung LFs and ATII cells were treated with 1,25D or 3-epi-1,25D (1 x 10(-10) to 1 x 10(-8) M) for 24 h, and cell proliferation, apoptosis, and differentiation were assessed. Both 1,25D and 3-epi-1,25D exhibited dose-dependent increases in expression of the key homeostatic epithelial-mesenchymal differentiation markers, increased LF and ATII cell proliferation, and decreased apoptosis. Furthermore, rat pups administered 1,25D from postnatal days 0 to 14 showed increased expressions of key LF and ATII cell differentiation markers, increased Bcl-2-to-Bax ratio as an index of decreased spontaneous alveolar LF and ATII cell apoptosis, increased alveolar count, and a paradoxical increase in septal thickness. We conclude that spatial- and temporal-specific actions of vitamin D play a critical role in perinatal lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and by modulating LF proliferation/apoptosis. These data not only provide the biological rationale for the presence of an alveolar vitamin D paracrine system, but also provide the first integrated molecular mechanism for increased surfactant synthesis and alveolar septal thinning during perinatal lung maturation.


Assuntos
Apoptose/efeitos dos fármacos , Calcitriol/farmacologia , Comunicação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Fibroblastos/citologia , Mesoderma/citologia , Alvéolos Pulmonares/citologia , Animais , Biomarcadores/metabolismo , Calcitriol/administração & dosagem , Calcitriol/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Mesoderma/efeitos dos fármacos , Modelos Biológicos , Comunicação Parácrina/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo
7.
Physiol Genomics ; 38(1): 1-6, 2009 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-19366785

RESUMO

In the postgenomic era, we need an algorithm to readily translate genes into physiologic principles. The failure to advance biomedicine is due to the false hope raised in the wake of the Human Genome Project (HGP) by the promise of systems biology as a ready means of reconstructing physiology from genes. like the atom in physics, the cell, not the gene, is the smallest completely functional unit of biology. Trying to reassemble gene regulatory networks without accounting for this fundamental feature of evolution will result in a genomic atlas, but not an algorithm for functional genomics. For example, the evolution of the lung can be "deconvoluted" by applying cell-cell communication mechanisms to all aspects of lung biology development, homeostasis, and regeneration/repair. Gene regulatory networks common to these processes predict ontogeny, phylogeny, and the disease-related consequences of failed signaling. This algorithm elucidates characteristics of vertebrate physiology as a cascade of emergent and contingent cellular adaptational responses. By reducing complex physiological traits to gene regulatory networks and arranging them hierarchically in a self-organizing map, like the periodic table of elements in physics, the first principles of physiology will emerge.


Assuntos
Evolução Biológica , Pulmão/fisiologia , Algoritmos , Comunicação Celular , Humanos , Pulmão/citologia , Biologia de Sistemas
8.
Med Hypotheses ; 72(5): 596-602, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19147298

RESUMO

In the post-genomic era, we must make maximal use of this technological advancement to broaden our perspective on biology and medicine. Our understanding of the evolutionary process is undermined by looking at it retrospectively, perpetuating a descriptive rather than a mechanistic approach. The reintroduction of developmental biologic principles into evolutionary studies, or evo-devo, allows us to apply embryologic cell-molecular biologic principles to the mechanisms of phylogeny, obviating the artificial space and time barriers between ontogeny and phylogeny. This perspective allows us to consider the continuum between the proximate and ultimate causes of speciation, which was unthinkable when looked at from the descriptive perspective. Using a cell-cell interactive 'middle-out' approach, we have gained insight to the evolution of the lung from the swim bladder of fish based on gene regulatory networks that generate both lung ontogeny and phylogeny, i.e. decreased alveolar size, decreased alveolar wall thickness, and increased alveolar wall strength. Vertical integration of cell-cell interactions predicts the adaptivity and maladaptivity of the lung, leading to novel insights for chronic lung disease. Since we have employed principles involved in all of development, this approach is amenable to all biologic structures, functions, adaptations, maladaptations, and diseases, providing an operational basis for preventive medicine.


Assuntos
Evolução Biológica , Medicina Preventiva , Humanos , Modelos Teóricos , Transdução de Sinais
9.
Integr Comp Biol ; 49(2): 142-54, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20607136

RESUMO

Physiology integrates biology with the environment through cell-cell interactions at multiple levels. The evolution of the respiratory system has been "deconvoluted" (Torday and Rehan in Am J Respir Cell Mol Biol 31:8-12, 2004) through Gene Regulatory Networks (GRNs) applied to cell-cell communication for all aspects of lung biology development, homeostasis, regeneration, and aging. Using this approach, we have predicted the phenotypic consequences of failed signaling for lung development, homeostasis, and regeneration based on evolutionary principles. This cell-cell communication model predicts other aspects of vertebrate physiology as adaptational responses. For example, the oxygen-induced differentiation of alveolar myocytes into alveolar adipocytes was critical for the evolution of the lung in land dwelling animals adapting to fluctuating Phanarezoic oxygen levels over the past 500 million years. Adipocytes prevent lung injury due to oxygen radicals and facilitate the rise of endothermy. In addition, they produce the class I cytokine leptin, which augments pulmonary surfactant activity and alveolar surface area, increasing selection pressure for both respiratory oxygenation and metabolic demand initially constrained by high-systemic vascular pressure, but subsequently compensated by the evolution of the adrenomedullary beta-adrenergic receptor mechanism. Conserted positive selection for the lung and adrenals created further selection pressure for the heart, which becomes progressively more complex phylogenetically in tandem with the lung. Developmentally, increasing heart complexity and size impinges precociously on the gut mesoderm to induce the liver. That evolutionary-developmental interaction is significant because the liver provides regulated sources of glucose and glycogen to the evolving physiologic system, which is necessary for the evolution of the neocortex. Evolution of neocortical control furthers integration of physiologic systems. Such an evolutionary vertical integration of cell-to-tissue-to-organ-to-physiology of intrinsic cell-cell signaling and extrinsic factors is the reverse of the "top-down" conventional way in which physiologic systems are usually regarded. This novel mechanistic approach, incorporating a "middle-out" cell-cell signaling component, will lead to a readily available algorithm for integrating genes and phenotypes. This symposium surveyed the phylogenetic origins of such vertically integrated mechanisms for the evolution of cell-cell communication as the basis for complex physiologic traits, from sponges to man.

10.
Cell Commun Insights ; 2: 17-25, 2009 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-25892907

RESUMO

In the post-genomic era the complex problem of evolutionary biology can be tackled from the top-down, the bottom-up, or from the middle-out. Given the emergent and contingent nature of this process, we have chosen to take the latter approach, both as a mechanistic link to developmental biology and as a rational means of identifying signaling mechanisms based on their functional genomic significance. Using this approach, we have been able to configure a working model for lung evolution by reverse-engineering lung surfactant from the mammalian lung to the swim bladder of fish. Based on this archetypal cell-molecular model, we have reduced evolutionary biology to cell communication, starting with unicellular organisms communicating with the environment, followed by cell-cell communication to generate metazoa, culminating in the communication of genetic information between generations, i.e. reproduction. This model predicts the evolution of physiologic systems-including development, homeostasis, disease, regeneration/repair, and aging- as a logical consequence of biology reducing entropy. This approach provides a novel and robust way of formulating refutable, testable hypotheses to determine the ultimate origins and first principles of physiology, providing candidate genes for phenotypes hypothesized to have mediated evolutionary changes in structure and/or function. Ultimately, it will form the basis for predictive medicine and molecular bioethics, rather than merely showing associations between genes and pathology, which is an unequivocal Just So Story. In this new age of genomics, our reach must exceed our grasp.

11.
Am J Physiol Lung Cell Mol Physiol ; 292(3): L608-11, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17085519

RESUMO

A functional, developmental, and comparative biological approach is probably the most effective way for arranging gene regulatory networks (GRNs) in their biological contexts. Evolutionary developmental biology allows comparison of GRNs during development across phyla. For lung evolution, the parathyroid hormone-related protein (PTHrP) GRN exemplifies a continuum from ontogeny to phylogeny, homeostasis, and repair. PTHrP signaling between the lung endoderm and mesoderm stimulates lipofibroblast differentiation by downregulating the myofibroblast Wnt signaling pathway and upregulating the protein kinase A-dependent cAMP signaling pathway, inducing the lipofibroblast phenotype. Leptin secreted by the lipofibroblast, in turn, binds to its receptor on the alveolar type II cell, stimulating surfactant synthesis to ensure alveolar homeostasis. Failure of the PTHrP/PTHrP receptor signaling mechanism causes transdifferentiation of lipofibroblasts to myofibroblasts, which are the hallmark for lung fibrosis. We have shown that by targeting peroxisome proliferator-activated receptor gamma, the downstream target for lipofibroblast PTHrP signaling, we can prevent lung fibrosis. We speculate that the recapitulation of the myofibroblast phenotype during transdifferentiation is consistent with lung injury as lung evolution in reverse. Repair recapitulates ontogeny because it is programmed to express the cross talk between epithelium and mesoderm through evolution. This model demonstrates how epithelial-mesenchymal cross talk, when seen as a recapitulation of ontogeny and phylogeny (in both a forward and reverse direction), predicts novel, effective diagnostic and therapeutic targets.


Assuntos
Redes Reguladoras de Genes , Homeostase , Pulmão/embriologia , Animais , Humanos , Pulmão/crescimento & desenvolvimento , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo
12.
J Steroid Biochem Mol Biol ; 89-90(1-5): 93-7, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15225753

RESUMO

Lung maturation before birth includes type II pneumocyte differentiation with progressive disappearance of glycogen content and onset of surfactant synthesis. We have shown previously that 1,25-(OH)2D3 increases surfactant synthesis and secretion by type II cells and decreases their glycogen content in fetal rat lung explants. Recently, the gene coding fructose 1,6 bisphosphatase (F1,6BP), a regulatory enzyme of gluconeogenesis, has been identified in type II cells and its promoter bears a Vitamin D response element. Present results show:The coexistence of type II cells at different stages of maturation. in rat fetal lung on day 21 of gestation (electron microscopy), and the association between maturation of type II cells and disappearance of their glycogen content. The immunogold labeling of all type II cells when using the 9A7g VDR-antibody, with significantly more abundant gold particles in cells exhibiting an intermediate glycogen content. The expression of F1,6BP mRNA in a human type II cell line (NCI-H441) and the increase of this expression after 18h incubation with 1,25-(OH)2D3 (10(-8)M). These results bring further evidence for a physiological role of 1,25-(OH)2D3 during type II pneumocyte maturation. Activation of F1,6BP may participate to the 1,25-(OH)2D3 action on surfactant synthesis via the gluconeogenesis pathway.


Assuntos
Calcitriol/farmacologia , Frutose-Bifosfatase/metabolismo , Pulmão/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Animais , Feminino , Frutose-Bifosfatase/genética , Imuno-Histoquímica , Pulmão/citologia , Pulmão/embriologia , Pulmão/enzimologia , Microscopia Eletrônica , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Acta Paediatr ; 92(9): 1062-7, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14599071

RESUMO

AIM: Human neonatal diaphragm development has not been extensively studied. Previous work in children and adults suggests that diaphragm thickness (t(di)) is in scale with body size such that maximal transdiaphragmatic pressure (P(dimax)) remains relatively constant. Such assessments have not been made in healthy term infants. This study was designed to evaluate the relationships among t(di), body dimensions and P(dimax) in healthy term infants. METHODS: It was hypothesized that in healthy term infants 1) t(di) is positively correlated with body size and 2) calculated P(dimax) is independent of body weight and length. Fifteen clinically stable term infants (8 males and 7 females) were recruited [birthweight (BW), 3.3 +/- 0.7 kg, (mean +/- SD); head circumference (HC), 33.7 +/- 2 cm; body length (BL) 50 +/- 3 cm; gestational age (GA) 39 +/- 1 wk; and postnatal age 1.7 +/- 0.8 day]. Ultrasound was used to visualize the diaphragm at the level of the zone of apposition and measure t(di). Standard techniques were used to measure the anthropometric dimensions of the rib cage. P(dimax) was calculated using the piston-in-cylinder model of diaphragm function. RESULTS: Significant correlations were found among t(di) and BW (R = 0.58), BL (R = 0.58) and HC (R = 0.65) but not between GA (R = 0.20). Larger infants tended to have thicker diaphragms and larger cross-sectional areas of the lower rib cage (A(ZAP)). For the group, calculated P(dimax) was independent of either body weight or length and was greater than that calculated for adults. CONCLUSION: It is concluded that diaphragm mass in healthy term infants is proportional to body size, whereas calcuated P(dimax) is independent of body size. Since calculated P(dimax) is greater than that predicted for adults, there may be perinatal diaphragm strengthening. This may assist the infant in generating sufficient pressure to overcome the enormous elastic and resistive loads imposed during perinatal pulmonary transition.


Assuntos
Diafragma/anatomia & histologia , Estatura , Peso Corporal , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Masculino
15.
Clin Lab Med ; 23(2): 361-83, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12848449

RESUMO

Fetal lung maturity testing represents a major milestone in perinatology. This article critically evaluates specific controversies regarding the methodologies used to measure pulmonary surfactant in AF and how well each of these techniques performs both in principle and application. The clinical utility of fetal lung maturity testing as it applies to particularly difficult complications of pregnancy is discussed. These technical and clinical issues are framed by the scientific and empiric evidence that is used as the rationale for such testing and its implementation in the effective management of preterm delivery.


Assuntos
Pulmão/embriologia , Organogênese/fisiologia , Diagnóstico Pré-Natal , Adulto , Feminino , Maturidade dos Órgãos Fetais/fisiologia , Humanos , Pulmão/metabolismo , Gravidez , Surfactantes Pulmonares/análise , Surfactantes Pulmonares/metabolismo , Valores de Referência , Fatores de Tempo
16.
Pediatr Pathol Mol Med ; 22(3): 189-207, 2003 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12746170

RESUMO

Parathyroid hormone-related protein (PTHrP) expression is necessary for differentiation of mesenchymal lipofibroblasts, which induce epithelial type II (TII) cell differentiation, both of which are necessary for alveolarization. PTHrP deficiency may be associated with bronchopulmonary dysplasia (BPD), characterized by truncation of alveolarization among preterm infants. This is supported by the baboon model of BPD (failure of alveolarization) that manifests PTHrP deficiency. We provide evidence that TII cell PTHrP expression is downregulated by alveolar overdistension, resulting in the transdifferentiation of lipofibroblasts to myofibroblasts, characterized by progressive loss of PTHrP receptor expression and triglyceride content, and sequential upregulation of alpha-smooth muscle actin (alphaSMA), typifying fibrosis. PTHrP reverses the downregulation of the PTHrP receptor and upregulation of alphaSMA, reverting myofibroblasts to a lipofibroblast genotype. When TII cells are co-cultured with lipofibroblasts, they proliferate and differentiate, expressing surfactant protein-B; in contrast, TII cells co-cultured with myofibroblasts fail to develop, mimicking the failed alveolarization associated with BPD. Treatment of myofibroblasts with 15-deoxy-Delta 12, 14 prostaglandinJ(2) (PGJ(2)) stimulates ADRP expression, reconstituting the lipofibroblast phenotype. PGJ(2)-treated myofibroblasts promote TII cell growth and surfactant protein-B expression, indicating that failed alveolarization due to transdifferentiation is reversible. We conclude that alveolar overdistension can cause fibroblast transdifferentiation, resulting in failed alveolarization.


Assuntos
Células Epiteliais/citologia , Fibroblastos/citologia , Pulmão/citologia , Animais , Animais Recém-Nascidos , Diferenciação Celular , Divisão Celular , Células Cultivadas , Dinoprosta/farmacologia , Células Epiteliais/metabolismo , Feminino , Feto , Fibroblastos/efeitos dos fármacos , Idade Gestacional , Pulmão/embriologia , Pulmão/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Papio , Proteína Relacionada ao Hormônio Paratireóideo/deficiência , Proteína Relacionada ao Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Perilipina-2 , Gravidez , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/embriologia , Alvéolos Pulmonares/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Respiração Artificial , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Mecânico
17.
Cell Biochem Biophys ; 37(3): 235-46, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12625629

RESUMO

Multicellular organisms have evolved in adaptation to the Earth's gravitational and oxygen environment. This epigenetic process is dependent on the capacity of mesodermal cells to act as mechanosensors that can conform, deform, and reform in adaptation to the organism's physical environment. Mechanical forces, such as hydrostatic pressure and gravity, play important roles in the embryonic development, homeostasis, and repair of lung and bone. We discuss the role of parathyroid hormone-related protein (PTHrP) as a mechanotransducer for stretch in these organs during normal development, particularly as it lends itself to homeostasis; we further demonstrate that "uncoupling" of such mechanisms may play a central role in injury repair, particularly as it relates to chronic diseases of lung and bone. Endothermal PTHrP signaling through its G-protein coupled receptor promotes normal cell-cell signaling that maintains the homeostatic phenotypes of lung and bone. Molecular disruption of the PTHrP/PTHrP receptor pathway from endoderm to mesoderm, because of such factors as volutrauma, hyperoxia, inflammation, and microgravity, alters intracellular signaling, causing maladaptive cellular changes, resulting in myofibroblast proliferation and granulation. Examples of such pathologic changes specifically related to this cellular/molecular mechanism of maladaptation are chronic lung disease and osteoporosis. We suggest a new paradigm that may help in the future creation of diagnostic and therapeutic modalities for a wide range of developmental and chronic diseases ranging from bronchopulmonary dysplasia in newborns to idiopathic pulmonary fibrosis and osteoporosis as a result of aging or microgravity.


Assuntos
Osso e Ossos/patologia , Pulmão/patologia , Animais , Diferenciação Celular , Divisão Celular , Endoderma/metabolismo , Fibroblastos/metabolismo , Humanos , Mesoderma/citologia , Mesoderma/metabolismo , Modelos Biológicos , Músculos/citologia , Proteína Relacionada ao Hormônio Paratireóideo , Hormônios Peptídicos/metabolismo , Fenótipo , Transdução de Sinais
18.
Am J Physiol Lung Cell Mol Physiol ; 283(1): L130-5, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12060569

RESUMO

Intrauterine lung development, culminating in physiological pulmonary surfactant production by epithelial type II (TII) cells, is driven by fluid distension through unknown mechanisms. Differentiation of alveolar epithelial and mesenchymal cells is mediated by soluble factors like parathyroid hormone-related protein (PTHrP), a stretch-sensitive TII cell product. PTHrP stimulates pulmonary surfactant production by a paracrine feedback loop mediated by leptin, a soluble product of the mature lipofibroblast (LF). When LFs and TIIs are stretched in coculture, there is a fivefold increase in surfactant phospholipid synthesis that can be "neutralized" by inhibitors of PTHrP or leptin, implicating a paracrine feedback loop in this mechanism. Stretching LFs stimulates PTHrP binding (2.5-fold) and downstream stimulation of triglyceride uptake quantitatively (15-25%) due to upregulation of adipose differentiation-related protein expression. Stretching TII cells increases leptin stimulation of their surfactant phospholipid synthesis threefold, suggesting that retrograde signaling by leptin to TII cells is also stretch sensitive. We conclude that the effect of stretch on alveolar LF and TII differentiation is coordinated by PTHrP, leptin, and their receptors.


Assuntos
Leptina/metabolismo , Comunicação Parácrina/fisiologia , Proteínas/metabolismo , Surfactantes Pulmonares/biossíntese , Animais , Células Cultivadas , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Expressão Gênica/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo , Perilipina-2 , Fosfatidilcolinas/biossíntese , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Hormônio Paratireóideo , Receptores de Hormônios Paratireóideos/metabolismo , Estresse Mecânico , Triglicerídeos/farmacocinética , Regulação para Cima/fisiologia
19.
Pediatrics ; 108(5): E91, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11694675

RESUMO

BACKGROUND: The diaphragm is the major inspiratory muscle in the neonate; however, human neonatal diaphragm development has not been extensively studied. We hypothesized that diaphragm thickness (t(di)) would be positively related to postmenstrual age (PMA), body weight, body length, head circumference, and nutritional intake. OBJECTIVES: To evaluate the evolution of diaphragm growth and motion in the healthy, preterm infant. METHODS: We used ultrasound to measure t(di) at the zone of apposition to the rib cage and diaphragm excursion (e(di)) during inspiration. Thirty-four stable, preterm infants (16 males and 18 females) between 26 and 37 weeks' PMA were studied during quiet sleep at weekly intervals until the time of discharge or transfer from the neonatal intensive care unit. All infants were clinically stable and not receiving ventilatory support. RESULTS: We found that 1) t(di) increased from 1.2 +/- 0.1 to 1.7 +/- 0.05 mm between 26 to 28 and 35 to 37 weeks' PMA; 2) t(di) was positively correlated with PMA (r = 0.40), body weight (r = 0.52), body length (r = 0.53), and head circumference (0.49), but not with postnatal nutritional intake (r = 0.09); and 3) e(di) decreased with increasing PMA. CONCLUSIONS: Our findings suggest that diaphragm development in premature infants scales with body dimensions. We speculate that the increase in t(di) with age is likely attributable to increased diaphragm muscle mass, and the reduced e(di) with age may be resulting from a reduction in chest wall compliance.


Assuntos
Diafragma/anatomia & histologia , Recém-Nascido Prematuro , Análise de Variância , Antropometria , Diafragma/diagnóstico por imagem , Diafragma/crescimento & desenvolvimento , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Ultrassonografia
20.
J Perinatol ; 21(8): 521-4, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11774012

RESUMO

OBJECTIVE: The use of continuous positive airway pressure (CPAP) in the treatment of a variety of neonatal respiratory conditions is associated with improvement in arterial oxygen saturation, decreased long-term morbidity, and an overall improvement in infant survival. We reasoned that CPAP might change diaphragm length by increasing end-expiratory lung volume (EEV), but the extent to which this occurs has not been assessed. This study was designed to evaluate (1) the extent to which CPAP shortens the diaphragm and (2) the relationship of diaphragm thickness and excursion with arterial oxygen saturation in spontaneously breathing preterm infants. STUDY DESIGN: Ultrasonographically (7.5 MHz transducer), diaphragm thickness and diaphragm excursion were measured in 12 stable preterm infants [birth weight 1120+/-225 g (mean+/-SD); study weight 1187+/-400 g; gestational age 29+/-1 week; postnatal age 10+/-8 days, six males and six females] at three levels of CPAP [1-3, 4-6, and 7-9 cm H(2)O (low, medium, and high, respectively)]. Heart rate, respiratory rate, and arterial oxygen saturation were simultaneously recorded. RESULTS: We found that diaphragm thickness and arterial oxygen saturation increased, and diaphragm excursion decreased significantly at higher levels of CPAP (p<0.05). The shortening of the diaphragm at the high levels of CPAP, calculated from the increase in diaphragm thickness, was 36% at EEV and 31% at end-inspiratory volume. CONCLUSION: We conclude that the improvement in arterial oxygen saturation with CPAP occurred despite the presence of a shorter and a less mobile diaphragm, and that other physiological and mechanical alterations accompanying the application of CPAP offset its negative effects on diaphragm function. We speculate that with excessive CPAP, however, diaphragm dysfunction along with the previously described adverse hemodynamic effects may outweigh its benefits on oxygenation.


Assuntos
Diafragma/anatomia & histologia , Recém-Nascido Prematuro , Respiração com Pressão Positiva , Feminino , Humanos , Recém-Nascido , Masculino , Oxigênio/sangue
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