Clara cell secretory protein decreases lung inflammation after acute virus infection

Clara cell secretory protein (CCSP) is an abundant 10-kDa polypeptide synthesized and secreted primarily by nonciliated bronchiolar epithelial cells in the mammalian lung. To determine the potential role of CCSP in pulmonary inflammation after acute viral infection, CCSP gene-targeted {CCSP-deficient [CCSP(−/−)]} mice were exposed to a recombinant E1- and E3-deficient adenoviral vector, Av1Luc1, intratracheally. Lung inflammation was markedly increased in CCSP(−/−) mice compared with wild-type control mice and was associated with an increased number of polymorphonuclear cell infiltrates and epithelial cell injury in both conducting airways and alveolar regions. Histological evidence of pulmonary inflammation in CCSP(−/−) mice was associated with increased production of cytokine (interleukin-1β and -6 and tumor necrosis factor-α) mRNA and protein, as well as chemokine (macrophage inflammatory protein-1α and -2 and monocyte chemoattractant protein-1) mRNA expression within the lung in response to adenoviral infection. Adenoviral-mediated gene transfer was decreased in CCSP(−/−) mice relative to wild-type mice as measured by luciferase enzyme activity in lung homogenates. The present study suggests that CCSP is involved in modulating lung inflammation during viral infection and supports a role for CCSP in lung host defense.

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CCSP deficiency does not alter surfactant homeostasis during adenoviral infection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.5.l983 ◽

1999 ◽

Vol 277 (5) ◽

pp. L983-L987 ◽

Cited By ~ 8

Author(s):

Machiko Ikegami ◽

Kevin S. Harrod ◽

Jeffrey A. Whitsett ◽

Alan H. Jobe

Keyword(s):

Pulmonary Inflammation ◽

Surfactant Protein ◽

Secretory Protein ◽

Clara Cell ◽

Capillary Leak ◽

Intratracheal Administration ◽

Adenoviral Infection ◽

Previous Infection ◽

Alveolar Capillary

Clara cell secretory protein (CCSP) deficiency in mice is associated with increased susceptibility to pulmonary inflammation after hyperoxia or viral infection. Because adenoviral exposure perturbs pulmonary surfactant homeostasis in vivo, we hypothesized that CCSP deficiency would influence surfactant metabolism after pulmonary infection. Alveolar and total lung saturated phosphatidylcholine pool sizes were similar in CCSP-deficient [CCSP(−/−)] and wild-type [CCSP(+/+)] mice before and 7 days after intratracheal administration of adenovirus. Radiolabeled choline and palmitate incorporation into saturated phosphatidylcholine was similar, and there was no alteration by previous infection 7 days before the incorporation measurements. Furthermore, CCSP deficiency did not influence clearance of [14C]dipalmitoylphosphatidylcholine and 125I-labeled recombinant surfactant protein C. Increased persistence of alveolar capillary leak was observed in CCSP(−/−) mice after adenoviral infection. Surfactant lipid homeostasis was not influenced by CCSP before or after administration of adenovirus to the lung. Persistence of alveolar capillary leak in CCSP(−/−) mice after adenovirus provides further evidence for the role of CCSP in the regulation of pulmonary inflammation.

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Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.01150.2004 ◽

2005 ◽

Vol 98 (4) ◽

pp. 1264-1271 ◽

Cited By ~ 33

Author(s):

Sawako Yoshikawa ◽

Takashige Miyahara ◽

Susan D. Reynolds ◽

Barry R. Stripp ◽

Mircea Anghelescu ◽

...

Keyword(s):

Lung Injury ◽

Bronchoalveolar Lavage ◽

Dry Weight ◽

High Volume ◽

Secretory Protein ◽

Clara Cell ◽

Wild Type ◽

Clara Cell Secretory Protein ◽

Ventilator Induced Lung Injury ◽

Volume Ventilation

Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA2 (cPLA2) and Clara cell secretory protein (CCSP), a modulator of cPLA2 activity, we compared lung injury with and without a PLA2 inhibitor in wild-type mice and CCSP-null mice (CCSP−/−) ventilated with high and low peak inflation pressures (PIP) for 2- or 4-h periods. After ventilation with high PIP, we observed significant increases in the bronchoalveolar lavage albumin concentrations, lung wet-to-dry weight ratios, and lung myeloperoxidase in both genotypes compared with unventilated controls and low-PIP ventilated mice. All injury variables except myeloperoxidase were significantly greater in the CCSP−/− mice relative to wild-type mice. Inhibition of cPLA2 in wild-type and CCSP−/− mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared with vehicle-treated mice of the same genotype. Membrane phospho-cPLA2 and cPLA2 activities were significantly elevated in lung homogenates of high-PIP ventilated mice of both genotypes but were significantly higher in the CCSP−/− mice relative to the wild-type mice. Inhibition of cPLA2 significantly attenuated both the phospho-cPLA2 increase and increased cPLA2 activity due to high-PIP ventilation. We propose that mechanical activation of the cPLA2 pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA2 pathway and reduction of proinflammatory products produced by this pathway.

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CLARA CELL SECRETORY PROTEIN-DEFICIENT MICE DIFFER FROM WILD-TYPE MICE IN INFLAMMATORY CHEMOKINE EXPRESSION TO OXYGEN AND OZONE, BUT NOT TO ENDOTOXIN

Experimental Lung Research ◽

10.1080/019021499270394 ◽

1999 ◽

Vol 25 (1) ◽

pp. 7-21 ◽

Cited By ~ 26

Author(s):

Carl J. Johnston

Keyword(s):

Secretory Protein ◽

Clara Cell ◽

Wild Type ◽

Chemokine Expression ◽

Clara Cell Secretory Protein ◽

Deficient Mice

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Exacerbation of Lung Radiation Injury by Viral Infection: The Role of Clara Cells and Clara Cell Secretory Protein

Radiation Research ◽

10.1667/rr3279.1 ◽

2013 ◽

Vol 179 (6) ◽

pp. 617-629 ◽

Cited By ~ 13

Author(s):

Casey M. Manning ◽

Carl J. Johnston ◽

Eric Hernady ◽

Jen-nie H. Miller ◽

Christina K. Reed ◽

...

Keyword(s):

Viral Infection ◽

Radiation Injury ◽

Secretory Protein ◽

Clara Cell ◽

Clara Cells ◽

Clara Cell Secretory Protein

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Regulation and function of CCSP during pulmonaryPseudomonas aeruginosainfection in vivo

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.3.l452 ◽

2000 ◽

Vol 279 (3) ◽

pp. L452-L459 ◽

Cited By ~ 46

Author(s):

Shinya Hayashida ◽

Kevin S. Harrod ◽

Jeffrey A. Whitsett

Keyword(s):

Epithelial Cells ◽

Pulmonary Inflammation ◽

Secretory Protein ◽

Clara Cell ◽

Polymorphonuclear Cells ◽

Wild Type ◽

Respiratory Epithelial Cells ◽

Factor Α ◽

Respiratory Epithelial

Clara cell secretory protein (CCSP) is a 16-kDa homodimeric polypeptide secreted by respiratory epithelial cells in the conducting airways of the lung. To assess the role of CCSP in bacterial inflammation and to discern whether CCSP expression is influenced by bacterial infection, CCSP-deficient [(−/−)] gene-targeted mice and wild-type mice were given Pseudomonas aeruginosa intratracheally. Infiltration by polymorphonuclear cells was significantly increased in the lungs of CCSP(−/−) mice 6 and 24 h after the administration of the bacteria. The number of viable bacteria isolated from the lungs in CCSP(−/−) mice was decreased compared with that in wild-type mice. Concentrations of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α were modestly increased after 6 and 24 h, respectively, in CCSP(−/−) mice. The concentration of CCSP protein in lung homogenates decreased for 1–5 days after infection and recovered by 14 days after infection. Likewise, CCSP mRNA and immunostaining for CCSP markedly decreased in respiratory epithelial cells after infection. CCSP deficiency was associated with enhanced pulmonary inflammation and improved killing of bacteria after acute pulmonary infection with P. aeruginosa. The finding that Pseudomonas infection inhibited CCSP expression provides further support for the concept that CCSP plays a role in the modulation of pulmonary inflammation during infection and recovery.

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CCSP modulates airway dysfunction and host responses in an Ova-challenged mouse model

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.281.5.l1303 ◽

2001 ◽

Vol 281 (5) ◽

pp. L1303-L1311 ◽

Cited By ~ 38

Author(s):

Shan-Ze Wang ◽

Cynthia L. Rosenberger ◽

Teresa M. Espindola ◽

Edward G. Barrett ◽

Yohannes Tesfaigzi ◽

...

Keyword(s):

Airway Epithelium ◽

Host Response ◽

Secretory Protein ◽

Allergic Airway Disease ◽

Clara Cell ◽

Myeloperoxidase Activity ◽

Wild Type ◽

Airway Reactivity ◽

Mucus Production

Clara cell secretory protein (CCSP) is synthesized by nonciliated bronchiolar cells in the lung and modulates lung inflammation to infection. To determine the role of CCSP in the host response to allergic airway disease, CCSP-deficient [(−/−)] mice were immunized twice with ovalbumin (Ova) and challenged by Ova (2 or 5 mg/m3) aerosol. After 2, 3, and 5 days of Ova aerosol challenge (6 h/day), airway reactivity was increased in CCSP(−/−) mice compared with wild-type [CCSP(+/+)] mice. Neutrophils were markedly increased in the bronchoalveolar lavage fluid of CCSP(−/−) Ova mice, coinciding with increased myeloperoxidase activity and macrophage inflammatory protein-2 levels. Lung histopathology and inflammation were increased in CCSP(−/−) compared with wild-type mice after Ova challenge. Mucus production, as assessed by histological staining, was increased in the airway epithelium of CCSP(−/−) Ova mice compared with that in CCSP(+/+) Ova mice. These data suggest a role for CCSP in airway reactivity and the host response to allergic airway inflammation and provide further evidence for the role of the airway epithelium in regulating airway responses in allergic disease.

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SP-A enhances viral clearance and inhibits inflammation after pulmonary adenoviral infection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.3.l580 ◽

1999 ◽

Vol 277 (3) ◽

pp. L580-L588 ◽

Cited By ~ 16

Author(s):

Kevin S. Harrod ◽

Bruce C. Trapnell ◽

Kazuhisa Otake ◽

Thomas R. Korfhagen ◽

Jeffrey A. Whitsett

Keyword(s):

Host Defense ◽

Lung Inflammation ◽

Cell Injury ◽

Recombinant Adenovirus ◽

Protein A ◽

Lavage Fluid ◽

Viral Clearance ◽

Polymorphonuclear Cells ◽

Adenoviral Infection ◽

Tnf Α

Surfactant protein A (SP-A) is a member of the collectin family of host defense molecules expressed primarily in the epithelial cells of the lung. To determine the role of SP-A in pulmonary adenoviral infection, SP-A-deficient (SP-A −/−) mice were intratracheally infected with a replication-deficient recombinant adenovirus, Av1Luc1. Lung inflammation was markedly increased in SP-A −/− compared with SP-A +/+ mice and was associated with increased hemorrhage and epithelial cell injury. Polymorphonuclear cells in bronchoalveolar lavage fluid (BALF) were increased in SP-A −/− mice after administration of adenovirus. Coadministration of adenovirus and purified human SP-A ameliorated adenoviral-induced lung inflammation in SP-A −/− mice. Concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were increased in BALF of SP-A −/− mice. Likewise, TNF-α, IL-6, macrophage inflammatory protein (MIP)-1α, monocyte chemotactic protein-1, and MIP-2 mRNAs were increased in lung homogenates from SP-A −/− mice 6 and 24 h after viral administration. Clearance of adenoviral DNA from the lung and uptake of fluorescent-labeled adenovirus by alveolar macrophages were decreased in SP-A −/− mice. SP-A enhances viral clearance and inhibits lung inflammation during pulmonary adenoviral infection, providing support for the importance of SP-A in antiviral host defense.

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