Hereditary Disorders of Alveolar Homeostasis in the Newborn

Jeffrey A. Whitsett MD , Timothy E. Weaver PhD , in The Newborn Lung, 2008

LUNG MATURATION AND SURFACTANT HOMEOSTASIS

Lung maturation is a complex procedure requiring establishment of highly branched tubes that atomic number 82 to a gas exchange area capable of supporting respiration following birth (one, 2). By 24 weeks gestation, during the canalicular-saccular transition of lung morphogenesis, respiratory epithelial cells in the lung periphery begin to undergo differentiation marked by accumulation and then utilization of glycogen stores for lipid synthesis. During the saccular stage of development, structural and biochemical maturation of the lung proceeds, associated with increasing vascularization of peripheral airspaces and thinning of the pulmonary mesenchyme. Interactions between mesenchymal fibroblasts and the epithelium outcome in the differentiation of type II epithelial cells, with their characteristic lamellar body inclusions, a storage granule for pulmonary surfactant. Blazon Ii cells differentiate to produce the highly differentiated squamous blazon I epithelial cells that class an increasing proportion of the saccular-alveolar surface of the lung with advancing gestation. In the normal lung, differentiation of the type 2 epithelial prison cell begins at 24–26 weeks gestation and tin be precociously induced by infection or hormonal stimulation with glucocorticoids (3). Lack of pulmonary surfactant in preterm infants causes respiratory distress syndrome (RDS), a major crusade of neonatal morbidity and mortality.

The biochemical maturation of type Two epithelial cells is marked past increased synthesis and storage of surfactant lipids highly enriched in phosphatidylcholine and phosphatidylglycerol. The enzymes regulating surfactant lipid synthesis, including fatty acid synthase, cytidylyltransferase, acyltransferase, and steroyl coA-desaturase, increase with advancing gestation and probably play important roles in the induction of surfactant lipid synthesis that occurs prior to nativity (iv). At the ultrastructural level, particulate glycogen becomes dispersed and is used as substrate for surfactant lipid synthesis. Lamellar bodies, the storage organelle of pulmonary surfactant, increase in number and size, existence initially observed within the pools of particulate glycogen at early stages of development. These intracellular inclusions become an increasingly prominent characteristic of type 2 epithelial cells with advancing gestation as lung phospholipid content increases prior to nascence. Lamellar bodies are multilamellated intracellular inclusions that are enriched in the surfactant lipids and the surfactant proteins, SP-B and SP-C. Prior to nascence, lamellar torso contents are secreted into the airways and can be measured in amniotic fluid. Surfactant secretion is induced during labor and with initiation of ventilation post-obit nativity.

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Western approach to labour

Suzanne Yates BA(Hons) DipHSEC MRSS(T) APNT PGCE(PCET) , in Pregnancy and Childbirth, 2010

Corticotropin-releasing hormone (CRH), glucocorticoids (cortisol), and dehydroepiandrosterone (DHEAS)

Dehydroepiandrosterone (DHEAS)

DHEAS is needed past the placenta to produce oestrogens, particularly estriol.

Cortisol

Cortisol stimulates fetal lung maturation and placental CRH. This is in contrast to the issue of increased cortisol on the hypothalamus where it has an inhibitory effect. In the placenta, glucocorticoids stimulate CRH receptors and increment CRH production.

Corticotropin-releasing hormone (CRH)

Placentallevels increase past upward to 50–100-fold in the last 6–8 weeks of gestation, paralleling the ascent in fetal cortisol (Majzoub & Karalis 1999). CHR receptors are establish on myometrium and it is thought that stimulation of these receptors may heighten myometrial contractility. CRH is idea to stimulate fetal ACTH which stimulates the fetal adrenal cortex to produce glucocorticosteroids such equally cortisol and DHEAS.

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Organogenesis in Development

David Warburton , ... Edwin Jesudason , in Electric current Topics in Developmental Biology, 2010

ii.2 The histological stages of lung development

Histologically, lung development and maturation has been divided into four stages: pseudoglandular, canalicular, terminal saccular, and alveolar (Fig. three.2).

Effigy 3.ii. Histology of mouse lung at feature stages of evolution. Embryonic mouse lung develops from pseudoglandular stage (E14.v) to canalicular stage (E16.5) and further terminal sac stage (E18.v and P1). Neonatal mouse lungs undergo alveolarization, resulting in the germination of many septa (P14). Finally, a mature honeycomb-like structure with alveoli surrounding alveolar ducts conferring normal respiratory structure and function is formed, as observed in the adult. Scale bar: 100   μm.

The pseudoglandular stage (five–17 weeks of human pregnancy, E9.five–xvi.vi days in mouse embryo). During this, the earliest developmental phase, epithelial tubes lined with cuboidal epithelial cells undergo branching morphogenesis and resemble an exocrine gland (hence the nomenclature). Notwithstanding, this fluid-filled primitive respiratory tree structure is too immature to support efficient gas commutation.

The canalicular stage (16–25 weeks of human pregnancy, E16.6–17.iv days in mouse embryo). The cranial function of the lung develops faster than the caudal part, resulting in partial overlap between this stage and the previous stage. During the canalicular stage, the respiratory tree is further expanded in diameter and length, accompanied by vascularization and angiogenesis along the airway. A massive increase in the number of capillaries occurs. The terminal bronchioles are then divided into respiratory bronchioles and alveolar ducts, and the airway epithelial cells are differentiated into peripheral squamous cells and proximal cuboidal cells.

The terminal saccular stage (24 weeks to tardily fetal period in human, E17.4 to postnatal 24-hour interval 5 (P5) in mouse). At that place is substantial thinning of the interstitium during the terminal saccular phase. This results from apoptosis too as ongoing differentiation of mesenchymal cells (Hashimoto et al., 2002; Lu et al., 2002). Additionally, at this stage, the alveolar epithelial cells (AECs) are more than clearly differentiated into mature squamous type I pneumocytes and secretory rounded type II pneumocytes bearing lamellar bodies that contain surfactant. The capillaries also abound quickly in the mesenchyme surrounding the saccules to form a complex network. In add-on, the lymphatic network in lung tissue becomes well adult during this phase. The thick wall of these saccules, also called principal septae, comprises lining epithelial cells on both sides of a connective tissue core, within which there is a double parallel network of capillaries. Toward the end of this phase, the fetal lung can support air exchange in prematurely built-in human neonates. Maturation of surfactant synthesis and secretion is a central factor in determining whether the newborn lung can sustain gas substitution without collapsing.

The alveolar phase (late fetal period to childhood in homo, P5–P30 in mouse). Alveolarization is the last stride of lung development. The bulk of the gas exchange surface is formed during this stage.

Genome-wide expression profiling has measured developing man lung transcriptomes in pregnancies terminated betwixt 7 and 22 weeks post conception (Kho et al., 2009). Within the 3,223 gene developing lung-characteristic subtranscriptome, transitions in gene expression correlated with some histological stages, as well as suggesting novel substages exist. For example, induction of surfactant gene expression identifies a "molecular transition" in the pseudoglandular phase.

Hence, the histological account of lung development is complimented by the molecular embryology that we consider in the next primary section of the review.

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Clinical Management

James M. Alexander , F.Gary Cunningham , in Chesley'due south Hypertensive Disorders in Pregnancy (Fourth Edition), 2015

Glucocorticoids

In attempts to heighten fetal lung maturation, glucocorticoids take been administered to women with severe hypertension who are remote from term. Treatment does non seem to worsen maternal hypertension and a decrease in the incidence of respiratory distress and improved fetal survival have been cited. That said, nosotros are aware of only one randomized trial of corticosteroids given to hypertensive women for fetal lung maturation. l This trial included 218 women with astringent preeclampsia between 26 and 34 weeks who were randomly assigned to be given betamethasone or placebo. Neonatal complications, including respiratory distress, intraventricular hemorrhage, and death, were decreased significantly when betamethasone was given compared with placebo. But in that location were 2 maternal deaths and eighteen stillbirths. We add together these findings to buttress our unenthusiastic acceptance of attempts to prolong gestation in many of these women. 51

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Perinatal Events and Their Influence on Lung Development and Office

Alan H. Jobe MD, PhD , ... Boris Westward. Kramer MD, PhD , in The Newborn Lung: Neonatology Questions and Controversies (Second Edition), 2012

Mechanisms of Inflammation-Mediated Lung Maturation

The mechanisms responsible for inflammation-induced lung maturation are not well understood. In the human, chorioamnionitis is associated with an increase in cortisol in cord blood collected at delivery, 111 and of course, glucocorticoids induce lung maturation. The clinical samples were from infants who had been exposed to chorioamnionitis and who were delivered as a result of preterm labor, which may represent a selected population—considering some women with chronic chorioamnionitis may non deliver prematurely. In fetal sheep, endotoxin-, IL-1–, or Ureaplasma-induced chorioamnionitis does not induce preterm labor, preterm commitment, or increases in fetal blood cortisol levels sufficient to induce lung maturation.

The minimal amount of Eastward. coli endotoxin given by intra-amniotic injection that will induce lung maturation in the fetal sheep is ane to four mg, and doses as loftier as 100 mg induce lung maturation without increasing the amount of lung inflammation or causing fetal injury or preterm delivery. 92,95 Doses of intra-amniotic endotoxin smaller than ane mg cause less inflammation and no lung maturation. In full general, the amount of lung inflammation induced past chorioamnionitis correlated with the amount of lung maturation. These results point that low amounts of lung inflammation do not induce lung maturation and that higher up some minimal level in that location is a dose-response relationship betwixt lung inflammation and lung maturation. Our grouping used a monoclonal antibiotic to the integrin CD18 to cake endotoxin-induced lung inflammation, which as well prevented lung maturation (Fig. 3-x). 112 In contrast, inflammation and lung maturation induced past IL-I was not blocked past this anti-CD18 antibiotic. This experiment links inflammation to lung maturation and further demonstrates that different proinflammatory agonists tin recruit inflammatory cells to the fetal lungs by unlike mechanisms.

This inflammation-maturation relationship was further examined with use of an IL-ane receptor blocker. 113 IL-1α is a potent inducer of chorioamnionitis, lung inflammation, and lung maturation. IL-1α likewise induces the expression of IL-1β in the chorioamnion, and cells in amniotic fluid and the fetal lung. When the IL-one receptor adversary IL-1ra was given into the amniotic fluid, about 80% of the lung inflammatory response to intra-amniotic endotoxin was blocked, and lung maturation was decreased. These experiments demonstrate that inflammation is essential to the lung maturation response. At that place currently is no information virtually what products of lung inflammation signal lung maturation. Presumably, mediators produced locally in the distal lung parenchyma, perhaps by granulocytes and/or monocytes, induce a signaling pour resulting in the mesenchymal and blazon II cell changes that result in lung maturation. Insight into this signaling sequence may provide clues for the development of clinically practical strategies to induce lung maturation.

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Perinatal Events and Their Influence on Lung Evolution and Injury

Suhas 1000. Kallapur , Alan H. Jobe , in The Newborn Lung (Third Edition), 2019

Mechanisms of Inflammation-Mediated Lung Maturation

The mechanisms responsible for inflammation-induced lung maturation are not well understood. The minimal amount of E. coli endotoxin given past intraamniotic injection that will induce lung maturation in the fetal sheep is 1 to iv mg, and doses every bit high every bit 100 mg induce lung maturation without increasing the amount of lung inflammation or causing fetal injury or preterm delivery. 112,116 In general, the amount of lung inflammation induced by chorioamnionitis correlated with the amount of lung maturation. Our group used a monoclonal antibody to the integrin CD18 to cake endotoxin-induced lung inflammation, which besides prevented lung maturation (Fig. two.12). 129 In dissimilarity, inflammation and lung maturation induced past IL-I was non blocked by this anti-CD18 antibody. This experiment directly links inflammation to lung maturation and further demonstrates that different proinflammatory agonists tin can recruit inflammatory cells to the fetal lungs past different mechanisms.

This inflammation-maturation human relationship was further examined with an IL-1 receptor blocker. 130 IL-1α and IL-1β are potent inducers of chorioamnionitis, lung inflammation, and lung maturation. When the IL-1 receptor antagonist IL-1ra was given into the amniotic fluid, most lxxx% of the lung inflammatory response to intraamniotic endotoxin was blocked, and lung maturation decreased. Since IL-1β is a potent cytokine, its secretion is exquisitely controlled in the cytoplasm by inflammasomes—a drove of interacting proteins that ultimately actuate caspase one, which cleaves pro-IL-1β to active IL-1β. When inflammasome NLRP3 was knocked out in mice, there was a significant reduction of lung IL-1β in neonatal mice in response to a hyperoxia challenge with a corresponding protection against BPD-similar changes in response to hyperoxia. 131 These experiments demonstrate that lung inflammation in response to multiple stimuli is mediated, at least in part, past IL-1 signaling and that lung inflammation tin can drive lung maturation responses. At that place currently is no information nearly which products of lung inflammation bespeak lung maturation. Presumably, mediators produced locally in the distal lung parenchyma, possibly past granulocytes and/or monocytes, induce a signaling cascade resulting in the mesenchymal and blazon II cell changes that issue in lung maturation. Insight into this signaling sequence may provide clues for the evolution of clinically applied strategies to induce lung maturation.

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Respiratory Disorders of the Newborn

J. Jane Pillow , Alan H. Jobe , in Pediatric Respiratory Medicine (Second Edition), 2008

INDUCTION OF FETAL LUNG MATURATION

Many hormones positively or negatively influence lung maturation in experimental systems. Agents that tin can accelerate lung maturation are corticosteroids, thyroid hormones, epidermal growth factor, and cyclic adenosine monophosphate. These substances may act by stimulating the synthesis of surfactant. 29 Only corticosteroids take been shown to subtract the incidence and severity of RDS consistently in randomized controlled trials. 11,12,30,31 At to the lowest degree two singled-out mechanisms promoting lung maturation take been identified: (one) a relatively rapid change (within fifteen hours) in lung structure that is associated with improved compliance, increased lung volume, and decreased capillary protein leak; and (ii) a slower, increased synthesis and secretion of surfactant by type Ii cells. 32 The delay betwixt corticosteroid assistants and upregulation of surfactant production and secretion limits the effectiveness of corticosteroids administered less than 24 hours before commitment. Although initial trials suggested that the combined antenatal use of corticosteroids with thyrotropin-releasing hormone (TRH) could further reduce the incidence or severity of RDS, 33 subsequent publications did non confirm the beneficial upshot of antenatal TRH. 34–36

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The Aging Human Lung: Age-Associated Changes in Structure and Office

Keith C. Meyer , in Handbook of Models for Man Aging, 2006

Introduction

After approximately two decades of postnatal lung maturation, the aging human lung has been estimated to gradually lose upward to 50% of its tissue mass over the remaining average lifespan of nonsmoking individuals who announced to be healthy and reside in developed countries. Although environmental factors may play a role in age-associated changes in the lung, loss of lung tissue and rubberband recoil, which some accept termed senile emphysema, appears to be a phenomenon that is linked to the normal aging process (Thurlbeck, 1991; Light-green and Pinkerton, 2004). Despite these age-associated changes, there is considerable interindividual variation in the caste and tempo of lung function decline, and these changes are unlikely to reach the signal of clinical respiratory dysfunction in healthy elderly persons. However, environmental and genetic factors likely play a significant role in the susceptibility of individuals and populations to historic period-associated lung function decline, and ecology factors may pb to clinical illness in susceptible individuals, even in nonsmokers. As the life span of humans gradually increases, it is conceivable that "normal" age-associated changes in lung construction and physiology may progress to the bespeak that they cause symptoms associated with respiratory dysfunction and have an touch on quality of life.

One of the most of import ecology factors associated with lung affliction in the elderly is cigarette smoking. Nearly one in five smokers who have normal αi-antitrypsin levels volition develop clinically significant chronic obstructive pulmonary disease (COPD) that generally makes its appearance in the sixth decade and beyond (Barnes, 2000). However, exposure to secondhand fume (Masi et al., 1988) or high levels of air pollution (Gauderman et al., 2005) early in life may significantly affect lung evolution. Such early on exposures may hold consequences for exposed individuals who achieve an advanced age and promote an accelerated decline in lung function despite a lack of primary tobacco smoking. Additionally, adaptive responses such every bit anti-protease or antioxidant defenses may be an of import determinant of susceptibility to diverse environmental factors both in age-associated changes in lung structure and function as well as in the development of clinical lung affliction (Taggare et al., 2005; Kelly et al., 2003). Because factors that include even low birth weight tin have pregnant consequences for postnatal lung development (Hoo et al., 2004), environmental influences, respiratory infections, genetic factors, and the bias presented by examining survivors in aged populations (which may not accurately reflect the population as a whole) can blur the separation of the changes in lung structure and function that are due purely to advanced historic period from changes that are caused past environmental exposures and genetic susceptibility.

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Babe RESPIRATORY DISTRESS SYNDROME

P.A. Dargaville , in Encyclopedia of Respiratory Medicine, 2006

Prevention of IRDS

Given the relationship between prematurity and IRDS, avoidance of preterm delivery is a logical way to reduce the incidence of IRDS. This said, the rates of preterm birth are in fact rise in the adult earth, fueled past a combination of factors including advanced maternal age, multiple pregnancy, and uptake of assisted conception. Farther, there is an increased preparedness in obstetric exercise to evangelize extremely preterm infants if the health of mother or fetus appears likely to be compromised past standing the pregnancy. Ablation of uterine contractions using tocolytic drugs does have a function in spontaneous preterm labor, if merely to permit sufficient fourth dimension for glucocorticoids administered to the female parent to accept an effect on the fetus.

Accepting that preterm nascence is often inevitable, the incidence and severity of subsequent IRDS can exist reduced by careful obstetric management, including acceleration of fetal maturation with glucocorticoids, abstention of traumatic delivery and/or intrapartum asphyxia, and awarding of advisable resuscitation to the infant immediately after nascence.

Antenatal glucocorticoid therapy

The impact of antenatal glucocorticoids on man fetal lung maturation was first documented in 1972, and this therapy is now widely applied in pregnancies threatening to cease prematurely. Pooled data from randomized controlled trials of antenatal glucocorticoids evidence a fifty% reduction in adventure of IRDS, a lesser severity of IRDS, and a lower mortality. The risks of intracranial hemorrhage and periventricular leukomalacia are also reduced. The benefits of glucocorticoids are credible at all gestations below 32 weeks, with a maximal effect if delivery occurred between 24   h and 7 days after administration. Antenatal glucocorticoid therapy is non associated with an increase in maternal, fetal, or neonatal infection, and appears to be safe fifty-fifty in the context of premature membrane rupture. The agents used are betamethasone (12   mg intramuscularly, two doses 24   h apart) and dexamethasone (6   mg intramuscularly, four doses 12   h autonomously), with the old resulting in the best neurological event for the premature baby.

Other agents that accept been administered antenatally for consecration of fetal lung maturation include thyrotropin-releasing hormone and ambroxol, with no conclusive evidence of benefit.

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Volume 1

Mary Ellen Avery , in Fetal and Neonatal Physiology (4th Edition), 2011

Surfactant Replacement

Glucocorticoids play an essential role in both lung maturation and the synthesis of lipid and protein components of pulmonary surfactants. 19,xx Noesis of hormonal influences in the timing of organ maturation began with the observations of Moog, 21 who in 1953 described the influence of the pituitary-adrenal system on the differentiation of phosphatase in the duodenum of the suckling mouse. Extensive experience with the employ of antenatal glucocorticoids to advance lung maturation followed the pioneering observations of Liggins, 22 who in 1969 noted the survival at a younger age of premature lambs of ewes that had received glucocorticoids before delivery. Many controlled clinical trials, which were reviewed in 1990 by Crowley and colleagues, 23 established both the condom and the efficacy of antenatal corticosteroids. Information technology appears that the effects of the combined utilise of prenatal corticosteroids and postnatal surfactant replacement are condiment. It is every bit if the steroids "condition" the lung past increasing the surface area over which the surfactants, which are instilled as a liquid into the trachea, can spread and exert their effects.

A new chapter in the history of surfactant discovery was written when Fujiwara and colleagues 24 presented their initial experience in an article in Lancet in 1980. They and others, notably Forrest Adams in Los Angeles and Goran Enhorning in Toronto, 25,26 spent the previous decade analyzing various mixtures of phospholipids in beast models and and so testing them in vitro. They finally decided that mixtures composed only of phospholipids would non have the requisite surface properties to stabilize airways effectively. Fujiwara and colleagues decided to use artificial surfactant (material derived from minced moo-cow lungs), which consisted of lipids and lipid-associated proteins. He enriched the fabric with added dipalmitoylphosphatidylcholine (DPPC) and called it TA surfactant, afterwards Tokyo, where the pharmaceutical house was located, and Akita, where he was working at the time.

The experience of Fujiwara and colleagues was distinguished from that of many investigators who attempted to treat surfactant-deficiency states with aerosolized DPPC; they used natural surfactants from cow lungs, and they instilled them as a liquid into the trachea and enhanced distribution by changing the position of the baby from one side to the other. Subsequently the instillation of 3 to v mL of material, they could demonstrate distribution in all the lobes of the lung and, impressively, a prompt increase in oxygenation. Thus it was evident that the material was distributed to the gas-exchanging surfaces of the lungs considering it resulted in a prompt and sustained improvement in oxygenation. Fujiwara and colleagues demonstrated that, in some infants, a unmarried instillation in the first 60 minutes of life or after the diagnosis of hyaline membrane disease could produce improved oxygenation that persisted for 2 to iii days, which was long enough for the baby to learn the capacity to synthesize endogenous surfactant.

These observations were non immediately acclaimed because the experience was non a prospective, randomized, controlled study. Nevertheless many investigators in various parts of the world in the mid-1980s were encouraged to conduct prospective, randomized, controlled trials, not only with TA surfactant only besides with other mixtures of materials, mostly those derived from calf lung lavage. Other sources of surfactant accept included human amniotic fluid, every bit evaluated by Merritt and colleagues, 27 and porcine lung extracts, which were studied by the Collaborative European Multicenter Study Grouping 28 in Europe. Meanwhile, TA surfactant was licensed in Japan in 1988 and is widely used. Other preparations, including a totally synthetic mixture, colfosceril, cetyl booze, and tyloxapol, also known as colfosceril palmitate, are licensed in the United states of america. Exosurf was invented past John Clements, who proposed that an booze (hexadecanol) be added to the principal phospholipid in pulmonary surfactant, DPPC. He also added tyloxapol to facilitate dispersion.

The natural surfactants from bovine or porcine sources accept been used extensively. Curt-term benefits are axiomatic with early administration, and continuing evaluation is under style to assess long-term benefits and safety.

Thus, in the years from identification of a deficiency of surfactants in the lungs of infants who died of hyaline membrane disease, to clinical trials, and now to the wide availability of natural and synthetic surfactants for treatment, the odyssey from bench to bedside to chemist's has been accomplished.

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