Chronic Lung Disease Of Newborns Research Articles

Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.

Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque (Macaca mulatta) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1β and tumor necrosis factor-α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.

Involvement of Hdac3-mediated inhibition of microRNA cluster 17-92 in bronchopulmonary dysplasia development

BackgroundThe incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances. Histone deacetylase 3 (Hdac3) has been reported to be a crucial regulator in alveologenesis. Hence, this study aims to investigate the mechanism of Hdac3 in the abnormal pulmonary angiogenesis and alveolarization of BPD.MethodsA hyperoxia-induced BPD model of was developed in newborn mice, and primary lung fibroblasts were isolated from adult mice. Hdac3 was knocked out in vivo and knocked down in vitro, while microRNA (miR)-17 was downregulated in vivo and in vitro to clarify their roles in abnormal pulmonary angiogenesis and alveolarization. Mechanistic investigations were performed on the interplay of Hdac3, miR-17-92 cluster, enhancer of zeste homolog 1 (EZH1), p65 and placental growth factor (Pgf).ResultsHdac3 was involved in abnormal alveolarization and angiogenesis in BPD mice. Further, the expression of the miR-17-92 cluster in BPD mice was downregulated by Hdac3. miR-17 was found to target EZH1, and Hdac3 rescued the inhibited EZH1 expression by miR-17 in lung fibroblasts. Additionally, EZH1 augmented Pgf expression by recruiting p65 thus enhancing the progression of BPD. Hdac3 augmented the recruitment of p65 in the Pgf promoter region through the miR-17/EZH1 axis, thus enhancing the transcription and expression of Pgf, which elicited abnormal angiogenesis and alveolarization of BPD mice.ConclusionsAltogether, the present study revealed that Hdac3 activated the EZH1-p65-Pgf axis through inhibiting miR-17 in the miR-17-92 cluster, leading to accelerated abnormal pulmonary angiogenesis and alveolarization of BPD mice.

The values of serum cytokines in chronic lung disease in newborn

Chronic lung disease in the newborn is a complication of mechanical ventilation. The diagnosis of chronic lung disease is made in children of over 36 post-conceptual weeks' age who still require additional oxygen and who have abnormal chest x-ray findings. This study was aimed at triaging newborns at risk of developing chronic lung disease. The operating study hypothesis was that the values of insulin-like growth factor I below 30 microg/L in the 33rd post-conceptual week were associated with the development of chronic lung disease. The above hypothesis was verified by a cohort, prospective study, which included preterm newborns of 33 gestational weeks' age or less who were hospitalised at the Department of Neonatology of the Clinical Centre of Montenegro from Aril 2008 to July 2009. The blood sample was taken in the 33rd post-conceptual week and the insulin-like growth factor value was determined by the method of enzyme immunoassay. Our study results confirmed the theory of statistically significant correlation of the length of pregnancy and birth body weight with insulin-like growth factor serum level. We did not find any statistically significant correlation between the insulin-like growth factor serum value and chronic lung disease in the newborn. It is possible that the insulin-like growth factor has a different role at various stages of pathogenesis of diseases of prematurity. We believe that by correcting the term for determining the levels we can get a significant correlation between low values of insulin-like growth factor -1 and chronic lung disease.

Association of development of chronic lung disease of newborns with neonatal colonization of Ureaplasma and cord blood interleukin‐8 level

The aim of the present study was to investigate the association of chronic lung disease (CLD), neonatal Ureaplasma colonization, and interleukin-8 (IL-8) level of cord blood in preterm infants. In 77 infants of <32 weeks gestation, the relationship between IL-8 level of cord blood, neonatal colonization of Ureaplasma, histological chorioamnionitis (CAM), and development of CLD was studied. Five infants died and 29 infants developed CLD. The CLD group had significantly lower gestation (mean ± SD: 26.6 ± 1.8 weeks) compared with the infants without CLD (28.9 ± 1.9 weeks, P < 0.0001). Logistic analysis showed that the development of CLD was associated with gestational age (odds ratio [OR], 0.5; 95% confidence interval (CI): 0.4-0.8) and Ureaplasma colonization (OR, 4.1; 95%CI: 1.2-14.4). Ureaplasma colonization was also associated with CAM (OR, 6.5; 95%CI: 1.8-23.5), absence of respiratory distress syndrome (OR, 6.2; 95%CI: 1.3-30.5), and development of CLD (OR, 4.0; 95%CI: 1.1-15.3). Elevated cord blood IL-8 ≥100 pg/mL was associated with female sex and the isolation of microorganisms (OR, 49.4; 95%CI: 4.6-525). The development of CLD defined by oxygen requirement at 36 weeks was associated with neonatal Ureaplasma colonization but not with IL-8 level of cord blood. Elevated cord blood IL-8 was associated with neonatal microorganisms isolation.

Chronic Inflammation and Amyloidogenesis in Alzheimer's Disease: The Emerging Role of Infection

The realization that pathogens can produce slowly progressive chronic diseases has resulted in new concepts of infectious diseases. A number of chronic diseases are caused by one or more infectious agents: e.g., stomach ulcer is caused by Helicobacter pylorii; chronic lung disease in newborns and chronic asthma in adults are both caused by Mycoplasmas; and, Chlamydia pneumoniae and some other pathogens have been associated with atherosclerosis. It has been known from a century that dementia and amyloidosis can be caused by chronic bacterial infection, namely by Treponema pallidum in the atrophic form of general paresis in syphilis. Alzheimer’s disease (AD), the most frequent cause of dementia, is a form of amyloidosis. The pathological mechanisms driving the accumulation of amyloid remain unclear. Pathogens (e.g., bacteria, viruses) are powerful stimulators of inflammation and were suggested to be one of the contributors in generating and sustaining chronic inflammation and amyloid deposition in AD. The concept is not new as it was discussed by Alzheimer and his colleagues a century ago. The fact that pathogens may suppress, subvert or evade host defenses and establish chronic or latent infection has received little attention in the past. During infection, active oxygen and nitrogen species generated by inflammatory cells may cause DNA damage, induce apoptosis, and modulate enzyme activities and gene expression. Depending upon the biology of the pathogen and the host defense mechanisms the organism can persist in the infected tissues, resulting in chronic inflammation. Pathogens may also elicit an autoimmune response without persistence of the initiating agent. The outcome of infection is as much determined by the genetic predisposition of the patient as by the virulence and biology of the infecting agent. Environmental factors and nutrition are critical determinants of disease expression as well. The goal of this special issue is to bring together a few of those scientists who have contributed significantly to this emerging field of research in order to guide new researchers toward highly productive investigations. Highest priority should be given for such research in the future. It may have major implications for public health, treatment, and prevention as adequate anti-bacterial and anti-viral drugs are available. Treatment of a bacterial infection and associated viral infection may result in regression and, if started early, prevention of disease. The impact on reducing health-care costs would be substantial.

Chronic lung disease in newborns

Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) occurs in preterm infants who require respiratory support in the first few days of birth. Apart from prematurity, oxygen therapy and assisted ventilation, factors like intrauterine/postnatal infections, patent ductus arteriosus, and genetic polymorphisms also contribute to its pathogenesis. The severe form of BPD with extensive inflammatory changes is rarely seen nowadays; instead, a milder form characterized by decreased alveolar septation due to arrest in lung development is more common. A multitude of strategies, mainly pharmacological and ventilatory, have been employed for prevention and treatment of BPD. Unfortunately, most of them have not been proved to be beneficial. A comprehensive protocol for management of BPD based on the current evidence is discussed here.

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstrated elevated bombesin-like peptide levels in infants that later developed BPD. In the 140-day hyperoxic baboon model of BPD, anti-bombesin antibody 2A11 abrogated lung injury. To test the hypothesis that bombesin-like peptides mediate BPD in extremely premature baboons (born at Gestational Day 125 and given oxygen pro re nata [PRN], called the 125-day PRN model), similar to "modern-day BPD." The 125-day animals were treated with 2A11 on Postnatal Day 1 (P1), P3, and P6. On P14 and P21, lungs were inflation-fixed for histopathologic analyses of alveolarization. Regulation of angiogenesis by bombesin was evaluated using cultured pulmonary microvascular endothelial cells. In 125-day PRN animals, urine bombesin-like peptide levels at P2-3 are directly correlated with impaired lung function at P14. Gastrin-releasing peptide (the major pulmonary bombesin-like peptide) mRNA was elevated eightfold at P1 and remained high thereafter. At P14, 2A11 reduced alveolar wall thickness and increased the percentage of secondary septa containing endothelial cells. At P21, 2A11-treated 125-day PRN animals had improved alveolarization according to mean linear intercepts and number of branch points per millimeter squared. Bombesin promoted tubulogenesis of cultured pulmonary microvascular endothelial cells, but cocultured fetal lung mesenchymal cells abrogated this effect. Early bombesin-like peptide overproduction in 125-day PRN animals predicted alveolarization defects weeks later. Bombesin-like peptide blockade improved septation, with the greatest effects at P21. This could have implications for preventing BPD in premature infants.

Certain type of chronic lung disease of newborns is associated with Ureaplasma urealyticum infection in utero

Recent studies of chronic lung disease (CLD) of newborns emphasize the contribution of antenatal infection. However, the association of Ureaplasma urealyticum infection and CLD has been controversial. The purpose of the present paper was to determine whether U. urealyticum is associated with chorioamnionitis (CAM) and a certain type of CLD. One hundred and five infants <32 weeks of gestation who were admitted to the neonatal intensive care unit at Jichi Medical School Hospital, who underwent both histological and microbiological examinations and who survived to discharge were included. CAM was determined by histological examination. Placenta, gastric and tracheal aspirates, and nasopharyngeal swabs were cultured for Mycoplasma and other microorganisms. CLD was defined as oxygen needed at 28 days of age with symptoms of persistent respiratory distress and hazy or emphysematous and fibrous appearance upon X-ray. CLD was further divided into two subtypes according to the presence of antenatal infection. CAM was associated with premature rupture of membrane (odds ratio [OR], 10.19; 95% confidence interval [CI]: 3.10-33.56), placental colonization of U. urealyticum (OR 6.73, 95%CI: 1.89-23.91), neonatal colonization of other microorganisms (OR 7.33, 95%CI: 1.22-44.13) and level of IgM (OR 1.06, 95%CI: 1.01-1.11). Comparisons between CLD and non-CLD patients showed that gestational age (OR 0.43, 95%CI: 0.30-0.61) and white blood cell count (WBC) at birth (OR 1.06, 95%CI: 1.01-1.11) were risk factors for CLD, while gestational age (OR 0.38, 95%CI: 0.23-0.64), neonatal colonization of U. urealyticum (OR 5.98, 95%CI: 1.17-30.6) and WBC (OR 1.08, 95%CI: 1.01-1.15) were independent risk factors for infection-related CLD compared with non-CLD. Within CLD, infection-related CLD was associated with neonatal colonization of U. urealyticum (OR 43.7, 95%CI: 2.84-673.8) and WBC (OR 1.27, 95%CI: 1.07-1.50). Placental colonization of U. urealyticum was significantly related to CAM; and neonatal colonization of U. urealyticum and leukocytosis at birth were risk factors for infection-related CLD.

Accelerated Thymic Maturation and Autoreactive T Cells in Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns triggered by oxygen and barotrauma, is characterized by arrested alveolarization. Increased levels of bombesin-like peptides shortly after birth mediate lung injury: anti-bombesin antibody 2A11 protects against BPD in two baboon models. The role of adaptive immunity in BPD has not been explored previously. Our goal was to test the hypothesis that thymic architecture and/or T-cell function is altered with BPD, leading to autoimmunity and immunodeficiency. Thymic structure was analyzed by histopathology of thymic architecture and immunohistochemistry for thymic maturation markers (terminal deoxynucleotidyl transferase, proliferating cell nuclear antigen, CD4, and CD8). Thymic cortical epithelial cells (nurse cells) were studied using HLA-DR and protein gene product 9.5 as markers. Functional analysis was performed with "mixed lymphocyte reaction" of thymocyte or splenocyte responder cells with autologous lung cells as the stimulators. 2A11 treatment attenuates thymic cortical involution in BPD animals, sustaining terminal deoxynucleotidyl transferase-positive prothymocytes and thymocyte proliferation. BPD animals have increased CD4(+) cells in thymic cortex and lung interstitium, which are reduced by 2A11. Conversely, cortical protein gene product 9.5/HLA-DR-positive thymic nurse cells are depleted in BPD animals, but are preserved by 2A11-treatment. Whereas fetal thymocytes and splenocytes respond to phythemagglutinin/ionomycin and to a lesser extent, to autologous lung, BPD thymocytes and splenocytes are phythemagglutinin/ionomycin-unresponsive, and yet react strongly to autologous lung. The 2A11 normalizes these responses. These observations suggest that bombesin-like peptides mediate premature thymic maturation and thymic nurse-cell depletion, leading to autoreactive T cells that could contribute to lung injury.

Hyperoxia regulates leukotriene (LT) receptor mRNA expression in the developing rat lung

Hyperoxia in newborn rats inhibits alveolarization and replicates many of the features of human newborn chronic lung disease (NCLD). Hyperoxia is known to cause an increase in LT expression in the lung and previous studies have demonstrated that LT administration during alveolarization can either arrest (LTB4) or accelerate (LTD4) lung development, suggesting they may be key mediators of this process. Our aim was to assess whether LTB4 receptor (BLT1 & BLT2) and LTD4 receptor (CysLT1 & CysLT2) mRNA expression is altered by hyperoxia. Methods Rat pups were placed in a normoxic (21% O2) or hyperoxic (>95% O2) environment from postnatal days 4 to 14. Pups were euthanized and lungs harvested on days 4, 6, 9, 12 and 14. Lung total RNA was extracted and analyzed using Real-Time RT-PCR. Data were analyzed by two-way ANOVA. Results The mRNA abundance of BLT1 and CysLT2 increased with age (p < 0.001) whilst BLT2 mRNA abundance decreased (p = 0.001). Each of these effects was accelerated by hyperoxia (p < 0.001). CysLT1 mRNA abundance also increased with time (p < 0.001) but hyperoxia generally decreased mRNA expression (p < 0.005). Conclusions All four LT receptors demonstrate clear changes in expression during alveolarization supporting the findings of previous research showing that LTs are involved in this process. The present study is the first to show that hyperoxia affects pulmonary LT receptor levels, suggesting that LTs are involved in the disruption of alveolarization caused by high oxygen concentrations and could be linked to NCLD. Supported by the Canadian Institutes of Health Research and the Hospital for Sick Children Foundation.

Immunomodulatory functions of the diffuse neuroendocrine system: implications for bronchopulmonary dysplasia.

Pulmonary neuroendocrine (NE) cells are believed to be the precursor of NE lung carcinomas, including well-differentiated (carcinoids) and moderately/poorly differentiated (atypical carcinoids and small-cell carcinomas, SCLCs) subtypes. In early studies, we determined mechanisms by which NE cell-derived peptides such as bombesin-like peptide (BLP) promote normal fetal lung development. Postnatally, BLP may normally regulate perinatal adaptation of the pulmonary circulation. However, elevated BLP levels in premature infants shortly after birth predict which infants are at high risk for developing bronchopulmonary dysplasia (BPD, chronic lung disease of newborns). An anti-BLP blocking antibody abrogates clinical and pathological evidence of lung injury in two baboon models of BPD. These observations indicate that BLP mediates lung injury in BPD, supporting a role for BLP as pro-inflammatory cytokines. We have directly tested the effects of BLP on eliciting inflammatory cell infiltrates in vivo. Surprisingly, mast cells are the major responding cell population. These data suggest that the diffuse NE system may be a newly recognized component of innate immunity in multiple organ systems. We speculate that overproduction of NE cell-derived peptides such as BLP may be responsible for a variety of chronic inflammatory disorders.

Induced p21Cip1 in premature baboons with CLD: implications for alveolar hypoplasia.

Aberrant pulmonary epithelial and mesenchymal cell proliferation occurs when newborns are treated with oxygen and ventilation to mitigate chronic lung disease. Because the cyclin-dependent kinase inhibitor p21 inhibits proliferation of oxygen-exposed cells, its expression was investigated in premature baboons delivered at 125 days (67% of term) and treated with oxygen and ventilation pro re nata (PRN) for 2, 6, 14, and 21 days. Approximately 5% of all cells expressed p21 during normal lung development of which <1% of these cells were pro-surfactant protein (SP)-B-positive epithelial cells. The percentage of cells expressing p21 increased threefold in all PRN-treated animals, but different cell populations expressed it during disease progression. Between 2 and 6 days of treatment, p21 was detected in 30-40% of pro-SP-B cells. In contrast, only 12% of pro-SP-B cells expressed p21 by 14 and 21 days of treatment, by which time p21 was also detected in mesenchymal cells. Even though increased epithelial and mesenchymal cell proliferation occurs during disease progression, those cells expressing p21 did not also express the proliferative marker Ki67. Thus two populations of epithelial and mesenchymal cells can be identified that are either expressing Ki67 and proliferating or expressing p21 and not proliferating. These data suggest that p21 may play a role in disorganized proliferation and alveolar hypoplasia seen in newborn chronic lung disease.

Estimation of individual genetic effects from binary observations on relatives applied to a family history of respiratory illnesses and chronic lung disease of newborns.

This paper considers methods for estimating the relationship between a binary response Y and the genetic effects responsible for a second binary trait Z. The responses Y are observed only for target individuals, and the responses Z are observed only for the relatives of these targets. The analysis consists of two parts. The first part concerns the analysis of the family data Z and the second part estimates the relation between the genetic effects and Y. For the family data, a generalized linear mixed model with a logit link and Gaussian genetic (random) effects is used. Estimates of the variances of the genetic effects are obtained by using a pseudo-profile log-likelihood method. Estimation of the log likelihood involves averaging over n-dimensional normal distributions, which is done by importance sampling. The methods used in the second part are straightforward. The methods are applied to a data set containing chronic lung disease (CLDN) responses of newborns and asthma (AS), allergy (AL), chronic bronchitis (CB) and eczema (EC) responses observed for the relatives of these newborns. The clinical question is whether genetic effects of AS, AL, CB, and EC have an effect on the risk for CLDN. It can be concluded that for AS, AL, CB, and EC, the influence of genetic effects is significant. However, these genetic predispositions have no significant effect on CLDN.

Infectious causes of chronic inflammatory diseases and cancer.

Powerful diagnostic technology, plus the realization that organisms of otherwise unimpressive virulence can produce slowly progressive chronic disease with a wide spectrum of clinical manifestations and disease outcomes, has resulted in the discovery of new infectious agents and new concepts of infectious diseases. The demonstration that final outcome of infection is as much determined by the genetic background of the patient as by the genetic makeup of the infecting agent is indicating that a number of chronic diseases of unknown etiology are caused by one or more infectious agents. One well-known example is the discovery that stomach ulcers are due to Helicobacter pylori. Mycoplasmas may cause chronic lung disease in newborns and chronic asthma in adults, and Chlamydia pneumoniae, a recently identified common cause of acute respiratory infection, has been associated with atherosclerosis. A number of infectious agents that cause or contribute to neoplastic diseases in humans have been documented in the past 6 years. The association and causal role of infectious agents in chronic inflammatory diseases and cancer have major implications for public health, treatment, and prevention.

New techniques for neonatal respiratory support

Considerable progress has been made in the management of respiratory distress in newborns since the introduction of positive pressure ventilation over 20 years ago. More recently, the introduction of surfactant and the increased use of steroids predelivery have led to a major increase iri survival in preterms with hyaline membrane disease. Conventional ventilation refers to the positive pressure respiratory support that is practised in newborn units. A wide variety of mechanical ventilators are currently in use in the UK and ventilator management policies vary widely between units with no consensus view as to the best approach. Trauma from ventilation is an important factor in the aetiology of the airway and lung damage seen in bronchopulmonary dysplasia (BPD). Asynchrony between the ventilator and the infant's respiration and the use of large tidal volumes to accomplish adequate ventilation are the major components of this trauma? In a study limiting tidal volume by constraints applied to the chest wall in an animal model the use of high airway pressures did not produce as much damage as when tidal volume was not limited) Therefore, changes in lung volume may be more important than changes in airway pressure in the production of lung injury. For this reason, the term volutrauma is preferred to barotrauma. In animals with healthy lungs 13 large tidal volume ventilation can damage the pulmonary capillary endothelium, alveolar and airway epithelium and basement membranes allowing fluid, protein and blood to leak into the airways, alveoli and lung interstitium. 1 This sequence is well described in the evolution of respiratory distress syndrome to chronic lung disease in newborns. Despite the excellent achievements in neonatal respiratory care, a number of infants continue to respond

HLA-A2 and Chronic Lung Disease in Neonates

Seventy-seven neonates weighing less than 1,500 g each were typed for HLA antigens. The phenotypes were correlated with the subsequent clinical course of the newborns. Forty-four (57%) of 77 newborns had an HLA-A2 antigen, whereas 194 (52%) of 376 unrelated adult controls possessed this same antigen. All 11 infants with roentgenographic evidence of chronic lung disease had HLA-A2 antigens, whereas 33 (50%) of 66 infants without HLA-A2 antigens did not have chronic lung disease. We conclude that the HLA-A2 antigen may be associated with susceptibility to chronic lung disease in newborns. (<i>JAMA</i>1982;248:1868-1869)