Collagen Scaffolding During Development and Its Deformation With Chronic Lung Disease

Thibeault, Donald W.; Mabry, Sherry M; Ekekezie, Ikechukwu I; Zhang, Xiaoming; Truog, William E.

doi:10.1542/peds.111.4.766

Cited by 103 publications

(88 citation statements)

References 22 publications

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“…In such patients, the thickness of collagen fibers directly correlated with the number of stable collagen cross-links (50), further supporting the notion that elevated lysyl oxidase activity might generate the thickened collagen fibers observed in the lungs of patients with BPD. This idea is also supported by the observation that elastic fibers in the lungs of lox 2/2 pups are thinner than in wild-type age-matched pups, and that collagen fibers in lox 2/2 pups were dispersed and loose (51), contrasting with the thickened, tightly bundled fibers observed in patients with BPD (11). Clearly, other mechanisms of elastin fiber assembly may also be affected in BPD.…”

Section: Discussionmentioning

confidence: 82%

“…Although many studies have examined the synthesis and production of ECM molecules in BPD, few studies to date have addressed the subsequent post-translational processing of these molecules, or the remodeling of the matrix itself (11,12). Therefore, in this study the expression and activity of lysyl oxidases, which play a key role in regulating the stability of the ECM, have been examined in an animal model of BPD, as well as in ventilated human neonates who have died either with BPD or at risk for BPD.…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

“…For example, an accumulation of elastic fibers has been observed in patients with classic BPD (9,10), and secondary collagen fibers in the saccular wall of patients who died with new BPD are ''thickened, tortuous, and disorganized'' (11). Excessive production and accumulation of elastin has also been reported in animal models of BPD.…”

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confidence: 99%

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Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Kumarasamy¹,

Schmitt²,

Nave³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-b) was preemptively blocked in mice exposed to hyperoxia using TGFb-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygeninjured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-b signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-b signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.

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Section: Discussionmentioning

confidence: 82%

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

See 1 more Smart Citation

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Kumarasamy¹,

Schmitt²,

Nave³

et al. 2009

Am J Respir Crit Care Med

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“…Chronic hyperoxia increases collagen deposition in spontaneously breathing neonatal mice (8), and mechanical ventilation of the immature lung is known to increase and alter the spatial pattern of collagen deposition (18,27,31). The effect of mechanical ventilation on collagen deposition is thought to be via a direct effect of mechanical strain on epithelial cells which signal interstitial fibroblasts to increase collagen production in vitro (32).…”

Section: Discussionmentioning

confidence: 99%

Ventilation and Oxygen: Dose-Related Effects of Oxygen on Ventilation-Induced Lung Injury

et al. 2010

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Preterm infants are at high risk of developing ventilator-induced lung injury. We have used an animal model of in utero ventilation (IUV) to investigate the separate effects of ventilation and acute oxygen exposure on the very immature lung. Fetal sheep were ventilated in utero at 110 d gestation for 6 h with 100, 21, or 0% (100% nitrogen) oxygen (n ϭ 5 each) and survived in utero, without further ventilation, until tissue collection at 118 d. Nonventilated 110 d and 118 d fetuses were used as controls. All IUV exposed fetuses had reduced secondary septal crest densities and increased elastin staining irrespective of the inspired oxygen concentration. IUV with 100% and 21% oxygen, but not 100% nitrogen, increased lung tissue volumes and myofibroblast differentiation and apoptosis within the distal lung parenchyma in a dose-dependent manner. This study shows that IUV without oxygen can reduce alveolarization, whereas ventilation with oxygen (6 h), even at levels found in air (21%), increases distal lung tissue volumes, elastin deposition, myofibroblast differentiation, and apoptosis. (Pediatr Res 67: 238-243, 2010) V ery preterm infants commonly require respiratory support after birth but debate exists as to the appropriate levels of inspired oxygen (FiO 2 ). As very preterm infants have an immature antioxidant system, they are susceptible to oxidative damage on exposure to high FiO 2 levels (1). Although high FiO 2 levels are often required to sustain appropriate oxygenation levels in very preterm infants, it is one of the greatest risk factors predisposing infants to bronchopulmonary dysplasia (BPD) (2). Indeed, prolonged exposure of immature lungs to hyperoxia can reproduce many structural changes that are characteristic of BPD (3-5). As high FiO 2 levels are often given with respiratory support, it is difficult to assess the relative contributions of these factors to neonatal lung injury (6,7).Models of hyperoxia-induced lung injury in newborns exist in many species (2,3,8,9). These studies show that chronic hyperoxia causes pathologic changes in lung structure, including inhibiting DNA synthesis, arresting alveolarization (8 -12), and remodeling of the pulmonary microvasculature thus increasing susceptibility of the newborn to pulmonary hypertension (2,13,14). Although mechanical ventilation can cause lung injury in the absence of high levels of oxygen (15,16), and the combined effect of ventilation and hyperoxia cause BPD-like alterations in lung morphology, hyperoxia is thought to have greater effects on lung pathology than ventilation per se (2). This implies a causative role for oxygen in the etiology of BPD, but the specific pathologic changes caused by oxygen are not clear. Furthermore, although, it is well established that chronic hyperoxia causes lung injury (8,17), little is known about the consequences of an acute exposure (Ͻ6 h) for very preterm infants. Indeed, many preterm infants are exposed to high FiO 2 levels for only a short period; particularly during the immediate newborn period...

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“…The reduced gas mixing efficiency (elevated LCI) observed in EP children may reflect some parenchymal or small airway changes, secondary to disruption of the interstitial collagen network that has been reported following neonatal positive pressure ventilation [29]. While the LCI has been shown to be an early indicator of airway disease Data expressed as mean¡SD Z-scores, unless otherwise stated.…”

Section: Nature Of Underlying Pathophysiologymentioning

confidence: 99%

Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age

Lum¹,

Kirkby²,

Welsh³

et al. 2010

European Respiratory Journal

154

140

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Advances in neonatal care have resulted in increased survival of children born extremely pre-term (EP). Nevertheless the incidence of bronchopulmonary dysplasia and longterm respiratory morbidity remains high. We investigated the nature of pathophysiological changes at 11 yrs of age to ascertain whether respiratory morbidity in EP children primarily reflects alterations in the lung periphery or more centralised airway function in this population.Spirometry, plethysmography, diffusing capacity, exhaled nitric oxide, multiple-breath washout, skin tests and methacholine challenge were used during laboratory-based assessments in a subgroup of the 1995 EPICure cohort and in controls.Results were obtained in 49 EP and 52 control children. Lung function abnormalities were found in 78% of EP children, with evidence of airway obstruction, ventilation inhomogeneity, gas trapping and airway hyperresponsiveness. Levels of atopy and exhaled nitric oxide were similar between the groups. Prior wheeze was associated with significant reductions in forced flows and volumes. By contrast, abnormalities of the lung periphery appear to be mediated primarily through EP birth per se.The prevalence of lung function abnormalities, which is largely obstructive in nature and likely to have long-term implications, remains high among 11-yr-old children born EP. Spirometry proved an effective means of detecting these persistent abnormalities.

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Collagen Scaffolding During Development and Its Deformation With Chronic Lung Disease

Cited by 103 publications

References 22 publications

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Ventilation and Oxygen: Dose-Related Effects of Oxygen on Ventilation-Induced Lung Injury

Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age

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