Surfactant Protein A Is a Principal and Oxidation-sensitive MicrobialPermeabilizing Factor in the Alveolar LiningFluid

Kuzmenko, Alexander I.; Wu, Huixing; Wan, Sijue; McCormack, Francis X.

doi:10.1074/jbc.m411344200

Cited by 25 publications

(26 citation statements)

References 20 publications

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“…Equivalent numbers of alveolar macrophages were plated (0.85 ϫ 10 6 ) in Hanks' balanced salt solution buffer, and 1 mM luminal (Sigma, A4685) was added for 10 min at constant temperature (37°C) (21). Zymosan (Sigma Z4250) was added to a final concentration of 0.35 mg/ml and chemiluminescence was monitored continuously for 90 min at 37°C in a luminometer (22).…”

Section: Kgf Pretreatment and Bronchoalveolar Lavage (Bal)mentioning

confidence: 99%

Keratinocyte Growth Factor Augments Pulmonary Innate Immunity through Epithelium-driven, GM-CSF-dependent Paracrine Activation of Alveolar Macrophages

Wu¹,

Suzuki

Carey

et al. 2011

Journal of Biological Chemistry

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Keratinocyte growth factor (KGF) is an epithelial mitogen that has been reported to protect the lungs from a variety of insults. In this study, we tested the hypothesis that KGF augments pulmonary host defense. We found that a single dose of intrapulmonary KGF enhanced the clearance of Escherichia coli or Pseudomonas aeruginosa instilled into the lungs 24 h later. KGF augmented the recruitment, phagocytic activity, and oxidant responses of alveolar macrophages, including lipopolysaccharide-stimulated nitric oxide release and zymosan-induced superoxide production. Less robust alveolar macrophage recruitment and activation was observed in mice treated with intraperitoneal KGF. KGF treatment was associated with increased levels of MIP1␥, LIX, VCAM, IGFBP-6, and GM-CSF in the bronchoalveolar lavage fluid. Of these, only GM-CSF recapitulated in vitro the macrophage activation phenotype seen in the KGF-treated animals. The KGF-stimulated increase in GM-CSF levels in lung tissue and alveolar lining fluid arose from the epithelium, peaked within 1 h, and was associated with STAT5 phosphorylation in alveolar macrophages, consistent with epithelium-driven paracrine activation of macrophage signaling through the KGF receptor/GM-CSF/GM-CSF receptor/ JAK-STAT axis. Enhanced bacterial clearance did not occur in response to KGF administration in GM-CSF ؊/؊ mice, or in mice treated with a neutralizing antibody to GM-CSF. We conclude that KGF enhances alveolar host defense through GM-CSFstimulated macrophage activation. KGF administration may constitute a promising therapeutic strategy to augment innate immune defenses in refractory pulmonary infections.Pneumonia accounts for over one million hospital discharges each year, and for about 5% of all inpatient hospital deaths (1-3). Although antibiotics typically speed recovery in bacterial pneumonias, even the most aggressive available therapies can fail to control advanced infections. The mortality and morbidity of serious respiratory infections could be substantially impacted by the development of broad-spectrum strategies to pharmacologically augment the innate immune defenses of the lung. Keratinocyte growth factor (KGF)2 is a potent epithelial mitogen and differentiation factor (4) that plays a central role in development and repair of injured epithelial tissues. KGF is produced exclusively by mesenchymal cells, including fibroblasts and smooth muscle cells, and acts only on epithelial cells (4), through ligation of an alternatively spliced FGF-2 tyrosine kinase receptor called FGFR2-IIIb. KGF has been reported to protect the lung from injury due to acid instillation (5), hyperoxia (6), bleomycin (7), and radiation exposure (8, 9), but less is known about KGF effects on defense against infectious challenges. The protective actions of KGF have been linked to stimulation of type II cell proliferation and differentiation, DNA repair, ion transport, and surfactant lipid and protein production (10 -15).This study was performed to determine whether KGF would enhance the clearance of...

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Section: Kgf Pretreatment and Bronchoalveolar Lavage (Bal)mentioning

confidence: 99%

Keratinocyte Growth Factor Augments Pulmonary Innate Immunity through Epithelium-driven, GM-CSF-dependent Paracrine Activation of Alveolar Macrophages

Wu¹,

Suzuki

Carey

et al. 2011

Journal of Biological Chemistry

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“…Oxidized surfactant displays inferior anti-inflammatory and surface tension lowering properties [66,67]. Reactive oxygen species alter the structure of surfactant lipids and proteins inactivating biophysical and immunological properties of surfactant components [68][69][70][71][72][73][74][75][76]. The macrophage scavenger receptors SR-A and MARCO clear oxidized surfactant lipids as a source of inflammation in the alveolus [77].…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Surfactant: An Immunological Perspective

Chroneos

Sever-Chroneos

Shepherd

2010

Cell Physiol Biochem

165

115

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“…Although this has been shown in many cases, it has not been shown for all of the specific proteins identified. We (57,60,61), and others (30) have shown in other studies that oxidation of SP-A inhibits its function. Similarly, the function of some antiproteases, such as ␣1-antitrypsin, is inhibited by oxidation (26).…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in the expression and oxidation of bronchoalveolar lavage proteins in the rat

Umstead¹,

Freeman²,

Chinchilli³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Umstead TM, Freeman WM, Chinchilli VM, Phelps DS. Age-related changes in the expression and oxidation of bronchoalveolar lavage proteins in the rat. Am J Physiol Lung Cell Mol Physiol 296: L14-L29, 2009. First published October 17, 2008 doi:10.1152/ajplung.90366.2008The incidence and severity of many lung diseases change with age. Some diseases, such as pneumonia, occur with increased frequency in children and the elderly. Proteins obtained by bronchoalveolar lavage (BAL) serve as the first line of defense against inhaled toxins and pathogens. Age-related changes in BAL protein expression and oxidative modification were examined in juvenile (1 mo), young adult (2 mo), and aged (18 mo) F344 rats using two-dimensional difference gel electrophoresis (2D-DIGE), matrix-assisted laser desorption ionization-time of flight/time of flight (MALDI-ToF/ToF) tandem mass spectrometry, and carbonyl immunoblotting. Using 2D-DIGE, we detected 563 protein spots, and MALDI-ToF/ToF identified 204 spots comprising 31 proteins; 21 changed significantly (17 increases) between juvenile and young adult or aged rats, but for 12 of these proteins, levels had a biphasic pattern, and levels in aged rats were less than in young adults. Relative carbonylation was determined by comparison of immunostaining with total protein staining on each oxidized protein blot. We found that aged rats had significantly increased oxidation in 13 proteins compared with juvenile rats. Many of the proteins altered in expression or oxidation level had functions in host defense, redox regulation, and protein metabolism. We speculate that low levels of expression of host defense proteins in juvenile rats and decreases in levels of these proteins between young adult and aged rats may predispose these groups to pneumonia. In addition, we have shown age-related increases in protein oxidation that may compromise host defense function in aged rats.aging; proteomics; host defense; carbonylation; proteolysis AGE IS A MAJOR FACTOR in the incidence of various lung diseases, particularly in the young and the old. Lung diseases, including chronic conditions such as emphysema and pulmonary fibrosis and acute lung diseases such as pneumonia, currently affect more than 35 million people in the U.S. Many of these diseases occur with increased frequency and severity in the elderly. However, pneumonia is also a serious problem in young children, both in developing countries, where it can be the leading cause of childhood mortality (48), and in developed countries, where morbidity is significant but mortality is low (16,43).Age also plays a role in how both humans and laboratory animals respond to pollution and various other insults. Aged organisms have an increased inflammatory response to oxidants, pollutants, and other insults (14,15,27,36,40) and are far more likely to become infected. Indeed, in the U.S., influenza and pneumonia are the fifth leading cause of death in patients over the age of 65 (37). Although it remains unclear why the elderly are more susceptible to pneumon...

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Surfactant Protein A Is a Principal and Oxidation-sensitive MicrobialPermeabilizing Factor in the Alveolar LiningFluid

Cited by 25 publications

References 20 publications

Keratinocyte Growth Factor Augments Pulmonary Innate Immunity through Epithelium-driven, GM-CSF-dependent Paracrine Activation of Alveolar Macrophages

Keratinocyte Growth Factor Augments Pulmonary Innate Immunity through Epithelium-driven, GM-CSF-dependent Paracrine Activation of Alveolar Macrophages

Pulmonary Surfactant: An Immunological Perspective

Age-related changes in the expression and oxidation of bronchoalveolar lavage proteins in the rat

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