Upregulation of Alveolar Epithelial Active Na
            <sup>+</sup>
            Transport Is Dependent on β
            <sub>2</sub>
            -Adrenergic Receptor Signaling

Mutlu, Gökhan M.; Dumasius, Vidas; Burhop, James; McShane, Pamela J.; Meng, Fanyong; Welch, Lynn C.; Dumasius, Andrew; Mohebahmadi, Nima; Thakuria, Gloria; Hardiman, Karen; Matalon, Sadis; Hollenberg, Steven M.; Factor, Phillip

doi:10.1161/01.res.0000125623.56442.20

Cited by 101 publications

(114 citation statements)

References 36 publications

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“…We delivered Cre recombinase to the lungs of mice by administering a high dose of a replication-deficient adenoviral vector in a surfactant vehicle, as described previously (Mutlu et al, 2004). Adenoviruses preferentially infect cells expressing the Cocksakie A receptor (CAR), a junctional adhesion molecule (JAM) localized to tight junctions in the airway and alveolar epithelium (Cohen et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Viraquest provided viral titers and excluded wild-type viral contamination of the viral vectors (negative PCR for glycoprotein E1). Mice were infected with adenoviral vectors (1610 9 pfu per animal) in 50% surfactant vehicle, balanced with TE buffer as previously described (Mutlu et al, 2004). The mice were housed in a barrier facility in microisolator cages for up to 60 days after the adenoviral infection.…”

Section: Adenoviral Infection Of Micementioning

confidence: 99%

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Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury

Urich

Eisenberg

Hamill

et al. 2011

Journal of Cell Science

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SummaryLaminins are heterotrimeric glycoproteins of the extracellular matrix that are secreted by epithelial cells and which are crucial for the normal structure and function of the basement membrane. We have generated a mouse harboring a conditional knockout of a3 laminin (Lama3 fl/fl ), one of the main laminin subunits in the lung basement membrane. At 60 days after intratracheal treatment of adult Lama3 fl/fl mice with an adenovirus encoding Cre recombinase (Ad-Cre), the protein abundance of a3 laminin in whole lung homogenates was more than 50% lower than that in control-treated mice, suggesting a relatively long half-life for the protein in the lung. Upon exposure to an injurious ventilation strategy (tidal volume of 35 ml per kg of body weight for 2 hours), the mice with a knockdown of the a3 laminin subunit had less severe injury, as shown by lung mechanics, histology, alveolar capillary permeability and survival when compared with Ad-Null-treated mice. Knockdown of the a3 laminin subunit resulted in evidence of lung inflammation. However, this did not account for their resistance to mechanical ventilation. Rather, the loss of a3 laminin was associated with a significant increase in the collagen content of the lungs. We conclude that the loss of a3 laminin in the alveolar epithelium results in an increase in lung collagen, which confers resistance to mechanical injury.

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Section: Discussionmentioning

confidence: 99%

Section: Adenoviral Infection Of Micementioning

confidence: 99%

Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury

Urich

Eisenberg

Hamill

et al. 2011

Journal of Cell Science

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“…Thus, if ENaC were to contribute to the regulation of airway function in CF, genetic variants of β 2 -AR would be predicted to modulate such regulation and would likely contribute to alveolar fluid accumulation and clearance, especially in injured lungs [35,36]. Although poor Na+ conductance has been suggested to contribute to reduced salt absorption in CF [37], recent studies of airways indicate that CF glands do not demonstrate excessive, ENaC-mediated fluid absorption [38].…”

Section: Discussionmentioning

confidence: 99%

Beta-2-adrenergic receptor polymorphisms in cystic fibrosis

Steagall

Barrow²,

Glasgow³

et al. 2007

Pharmacogenetics and Genomics

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Objectives-Cystic fibrosis (CF), an autosomal recessive disease affecting the lung, pancreas, gut, liver, and reproductive tract, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cyclic adenosine 3′, 5′ monophosphateregulated chloride channel. The variability of disease progression among patients with CF suggests effects of genetic modifiers of disease. Beta-2 adrenergic receptors (β 2 AR), which are abundant in airway epithelial cells, accelerate the formation of cyclic adenosine 3′, 5′ monophosphate, which can modulate CFTR activity and affect smooth muscle contractility. We tested the hypothesis that genetic variants of the β 2 AR gene, which have been shown to influence receptor desensitization, are more frequent in patients than in controls.Methods-We genotyped 130 adult CF patients and 1 : 1 age-matched, sex-matched, and ethnicity-matched normal volunteers for Gly 16 Arg and Gln 27 Glu β 2 AR.Results-We found that CF patients were more likely than controls to be Gly 16 homozygotes (48 and 32%, respectively) (P < 0.01) and Glu 27 homozygotes (29 and 10%, respectively) (P < 0.01). Conclusions-Our results, showing a higher frequency of Gly 16 and Glu 27 β 2 AR alleles in adult CF patients than in the control population, contrast with data from children with CF, who are reported to have lower frequency of Gly 16 and similar frequency of G1u 27 , and with data from young adults with CF, who showed no differences in frequencies of β 2 AR variants. The Gly 16 Glu 27 variant of β 2 AR may have properties that lead to enhanced β 2 AR function, resulting in the upregulation of CFTR activity and the improvement of CF disease.

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“…Mice were infected with adenoviral vectors in 50% surfactant vehicle, balance TE buffer as previously described, and were exposed to hyperoxia 7 days later (adenoviral SOD2) or 30 days later (adenoviral Cre) (29). Localization of the Ad-SOD2 is shown in Figure E1 in the online supplement.…”

Section: Adenoviral Infection Of Cells and Micementioning

confidence: 99%

“…Histology, lung wet-to-dry weight ratios, and bronchoalveolar lavage analysis were measured as previously reported (29).…”

Section: Measurement Of Reactive Oxygen Speciesmentioning

confidence: 99%

Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury

Budinger¹,

Mutlu²,

Urich³

et al. 2011

Am J Respir Crit Care Med

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Rationale: Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown. Objectives: To determine whether oxidant-mediated activation of the intrinsic or extrinsic apoptotic pathway contributes to the development of acute lung injury. Methods: Exposure of tissue-specific or global knockout mice or cells lacking critical components of the apoptotic pathway to hyperoxia, a well-established mouse model of oxidant-induced lung injury, for measurement of cell death, lung injury, and survival. Measurements and Main Results: We found that the overexpression of SOD2 prevents hyperoxia-induced BAX activation and cell death in primary alveolar epithelial cells and prolongs the survival of mice exposed to hyperoxia. The conditional loss of BAX and BAK in the lung epithelium prevented hyperoxia-induced cell death in alveolar epithelial cells, ameliorated hyperoxia-induced lung injury, and prolonged survival in mice. By contrast, Cyclophilin D-deficient mice were not protected from hyperoxia, indicating that opening of the mitochondrial permeability transition pore is dispensable for hyperoxia-induced lung injury. Mice globally deficient in the BH3-only proteins BIM, BID, PUMA, or NOXA, which are proximal upstream regulators of BAX and BAK, were not protected against hyperoxia-induced lung injury suggesting redundancy of these proteins in the activation of BAX or BAK. Conclusions: Mitochondrial oxidant generation initiates BAX-or BAK-dependent alveolar epithelial cell death, which contributes to hyperoxia-induced lung injury.

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Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling

Cited by 101 publications

References 36 publications

Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury

Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury

Beta-2-adrenergic receptor polymorphisms in cystic fibrosis

Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury

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Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on β 2 -Adrenergic Receptor Signaling

Cited by 101 publications

References 36 publications

Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury

Lung-specific loss of the laminin α3 subunit confers resistance to mechanical injury

Beta-2-adrenergic receptor polymorphisms in cystic fibrosis

Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury

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Product

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Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling