Hyperoxia increases airway cell S-phase traversal in immature rats in vivo.

Hershenson, Marc B.; Kelleher, Michael D.; Naureckas, Edward T.; Abe, Mark K.; Rubinstein, Valeria J.; Zimmermann, Anne; Bendele, Alison M.; McNulty, John A.; Panettieri, Reynold A.; Solway, Julian

doi:10.1165/ajrcmb.11.3.8086167

Cited by 33 publications

(20 citation statements)

References 22 publications

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“…Studies in juvenile rats exposed to hyperoxia (F I O 2 > 0.95) for 8 days demonstrated increased ASM mitosis and thickness (22) which would be expected to confer increased airway resistance given similar stimuli, compared with airways possessing normal ASM thickness. ASM cell proliferation is increased by mast cell products tryptase and platelet derived growth factor (23).…”

Section: Discussionmentioning

confidence: 99%

Mast Cells Mediate Hyperoxia-Induced Airway Hyper-Reactivity in Newborn Rats

et al. 2010

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Premature infants are at increased risk of developing airway hyper-reactivity (AHR) after oxidative stress and inflammation. Mast cells contribute to AHR partly by mediator release, so we sought to determine whether blocking mast cell degranulation or recruitment prevents hyperoxia-induced AHR, mast cell accumulation, and airway smooth muscle (ASM) changes. Rats were exposed at birth to air or 60% O 2 for 14 d, inducing significantly increased AHR in the latter group, induced by nebulized methacholine challenge and measured by forced oscillometry.

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Section: Discussionmentioning

confidence: 99%

Mast Cells Mediate Hyperoxia-Induced Airway Hyper-Reactivity in Newborn Rats

et al. 2010

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“…Given the marked changes that occur in the airways during the transition to extrauterine life, it can be speculated that physical and biochemical mechanisms unique to the airways themselves positively influence the growth state of these cells during the early postpartum period. Additionally, although our data appear to represent the first complete analysis of cellular replication during development in large airways, the replication indices reported here for at least one time point in development (ppd 30) are consistent with those observed in an earlier study of air- way epithelial cell and SMC replication indices of weanling rats exposed to normoxic or hyperoxic conditions (41).…”

Section: Discussionsupporting

confidence: 90%

Relationship between Perlecan and Tropoelastin Gene Expression and Cell Replication in the Developing Rat Pulmonary Vasculature

Belknap

Weiser‐Evans²,

Grieshaber³

et al. 1999

Am J Respir Cell Mol Biol

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Smooth-muscle-cell (SMC) replication and extracellular matrix protein expression are two vital and interrelated processes necessary for normal development of the vasculature. To understand better the nature of this relationship in the developing rat lung, we investigated the relationship between SMC proliferation and the expression of perlecan, a basement membrane (BM) heparan sulfate proteoglycan implicated in the control of SMC growth and differentiation, and tropoelastin (TE), a structural matrix protein not known to influence directly the replicative state of SMCs. Using bromodeoxyuridine (BrdU) incorporation to assess DNA synthesis, we first established the time course of SMC proliferation in the hilar pulmonary artery (PA) from embryonic to adult life. We found a labeling index of > 80% during the embryonic period (embryonic Day 13 [e13] to fetal Day 18 [f18]), a dramatic decline to approximately 40% during the fetal period of development, and a steady decrease in proliferation rates following birth such that, by 30 d of age, a labeling index of < 2% was noted. Using in situ hybridization, we found that although peak expression of both perlecan and TE messenger RNA (mRNA) occurred in the fetal and early postnatal periods following the major decrease in cell replication, TE mRNA expression was clearly observed in the PA as early as embryonic Day 14, whereas perlecan transcripts were virtually undetectable until fetal Day 19. Therefore, to evaluate further the relationship between cell replication and perlecan and/or TE gene expression, we used a combined in situ hybridization/BrdU immunohistochemistry technique and demonstrated that, on an individual cell basis, perlecan message was predominantly expressed by nonreplicating (BrdU-negative) PA, whereas TE mRNA was equally expressed in replicating and nonreplicating PA SMCs. Interestingly, a very similar pattern of replication and relationship to perlecan and TE mRNA expression was noted in airway SMCs and epithelial cells. Thus, in the lung as a whole, maximal expression of both the BM protein perlecan and the interstitial matrix protein TE occurs coordinately and follows the period of maximal SMC proliferation. However, in individual SMCs, perlecan mRNA expression varies inversely with DNA synthesis, whereas TE mRNA expression appears independent of the proliferative state of the cell.

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“…In addition, profibrotic cytokines are increased in bronchoalveolar fluid of preterm infants who developed chronic lung disease (21). IGF-1 and other profibrotic cytokines lead to airway remodeling with increased thickness of interstitial matrix (22) (23). The airway hyper-responsiveness is primarily a function of contraction of airway smooth muscles (24).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-I Signaling Mechanisms, Type I Collagen and Alpha Smooth Muscle Actin in Human Fetal Lung Fibroblasts

Chetty¹,

Cao²,

Nielsen³

2006

Pediatr Res

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ABSTRACT:Bronchial wall remodeling is a major morbidity component in oxidant injury in bronchopulmonary dysplasia (BPD) and asthma. Hypothesis: IGF-1 enhances alpha smooth muscle expression and collagen synthesis in developing lung fibroblasts leading to fibrosis through nuclear NF-k B -dependent transcription. We studied NF-k B dependent transcription by transfecting HFLF with a NF-k B responsive promoter driving the luciferase gene and treating with IGF-1 (100 ng/mL) and measuring luciferase activity. We exposed cells to the PI-3 kinase inhibitor or the Erk1/2 inhibitor one hr before stimulating with IGF-1. We also used IGF-1 receptor antibody to inhibit the action of IGF-1 and studied its effect on alpha-sma and type I collagen. IGF-1 treatment significantly increased luciferase activity. This was attenuated by PI-3 kinase and MAP-Kinase inhibitors. Western blot analysis showed PI-3 kinase mediates IGF-1 activation of NF-k B independent of I K B phosphorylation. We found an up-regulation of phospho NF-kB in the nuclear extract compared with total NFKB showing that IGF-1 regulates NF-k B transcriptional activity downstream of NF-k B nuclear translocation. IGF-1-induced increase in alpha-sma expression and type-I collagen was significantly inhibited by pretreatment with LY294002 and IGF-1 receptor antibody. IGF-1 cell signaling leading to collagen synthesis in fetal lung fibroblasts is mediated by PI3 Kinase acting through NF-k B in HFLF. (Pediatr Res 60: 389-394, 2006) I n asthma, chronic inflammation leads to pathologic changes in the airways with marked remodeling (1). An increased number of myofibroblasts beneath the bronchial epithelial basement membrane has been described in asthma. Bronchial biopsies of asthmatic patients show thickening of the subepithelial layer due to the deposition of fibrillar collagen (2). The production of mediators by epithelial cells in close proximity to myofibroblasts during epithelial repair after repeated damage is one possible mechanism for airway remodeling (3). IGF-1 and IGF binding proteins (IGFBPs) are active in the pulmonary cellular environment to modulate cell proliferation and function (4). IGF-1 and its receptor, IGF-1R, are also known to modulate repair processes after lung injury (5). Others and we have observed that IGF-1R expression is more intense in areas of increased cell proliferation in developing lung (6,7). These studies prompted us to investigate the hypothesis that IGF-1 mediated signaling in developing lung cells may induce some of the phenotypic changes that are observed in asthma. We examined the signaling pathway activated by IGF-1 in fetal lung fibroblasts leading to an increase in myofibroblast proliferation and collagen synthesis, and whether this involves nuclear NF-kappaB (NF-k B)-dependent transcription. MATERIALS AND METHODSReagents were obtained as follows: Recombinant IGF-1 and IGF-1 receptor antibody were purchased from R&D Systems (Minneapolis, MN). Goat antirabbit IgG was purchased from Upstate Biotechnology (Charlottesville, VA). Penic...

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Hyperoxia increases airway cell S-phase traversal in immature rats in vivo.

Cited by 33 publications

References 22 publications

Mast Cells Mediate Hyperoxia-Induced Airway Hyper-Reactivity in Newborn Rats

Mast Cells Mediate Hyperoxia-Induced Airway Hyper-Reactivity in Newborn Rats

Relationship between Perlecan and Tropoelastin Gene Expression and Cell Replication in the Developing Rat Pulmonary Vasculature

Insulin-like Growth Factor-I Signaling Mechanisms, Type I Collagen and Alpha Smooth Muscle Actin in Human Fetal Lung Fibroblasts

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