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

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: a determinant of PCB bioaccumulation in mammals

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1996.271.4.l656 ◽

1996 ◽

Vol 271 (4) ◽

pp. L656-L664 ◽

Cited By ~ 14

Author(s):

B. R. Stripp ◽

J. Lund ◽

G. W. Mango ◽

K. C. Doyen ◽

C. Johnston ◽

...

Keyword(s):

Polychlorinated Biphenyl ◽

Protein A ◽

Secretory Protein ◽

Clara Cell ◽

Clara Cell Secretory Protein ◽

Pcb Metabolites ◽

Normal Physiological Function ◽

Deficient Mice ◽

Lung And Kidney

Clara cell secretory protein (CCSP) is a product of nonciliated cells of the conducting airway epithelium. The normal physiological function of CCSP is unknown. However, the ability of CCSP to bind small lipophilic molecules, such as steroid hormones and certain pollutants, has led to speculation that this protein may mediate the biological accumulation of potentially harmful polychlorinated biphenyl (PCB) metabolites within the lung. To investigate the contribution of CCSP in the in vivo accumulation of methylsulfonyl-PCB, a line of mice was established that were homozygous for a null allele of the CCSP gene. CCSP-deficient mice were healthy and fertile, with no gross physiological or pathological abnormalities Parenteral challenge with the PCB metabolite 4-methylsulfonyl-2,2',4',5,5'-pentachlorobiphenyl (MeSO2-PCB) demonstrated that CCSP-deficient mice no longer accumulate this class of pollutants within lung and kidney tissues. These data demonstrate that CCSP is the determinant for MeSO2-PCB accumulation within mice and support the notion that bioconcentration of MeSO2-PCB pollutants occurs at sites of CCSP localization, such as the respiratory and reproductive tracts of humans.

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Clara cell secretory protein decreases lung inflammation after acute virus infection

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.275.5.l924 ◽

1998 ◽

Vol 275 (5) ◽

pp. L924-L930 ◽

Cited By ~ 30

Author(s):

Kevin S. Harrod ◽

Amber D. Mounday ◽

Barry R. Stripp ◽

Jeffrey A. Whitsett

Keyword(s):

Viral Infection ◽

Lung Inflammation ◽

Cell Injury ◽

Pulmonary Inflammation ◽

Secretory Protein ◽

Clara Cell ◽

Wild Type ◽

Monocyte Chemoattractant Protein 1 ◽

Adenoviral Infection ◽

Clara Cell Secretory Protein

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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GENE EXPRESSION OF MATRIX METALLOPROTEINASES IN CLARA-CELL SECRETORY PROTEIN-DEFICIENT MICE EXPOSED TO CIGARETTE SMOKE

Inhalation Toxicology ◽

10.1080/08958370050165175 ◽

2000 ◽

Vol 12 (sup3) ◽

pp. 301-305

Author(s):

Yasuo Morimoto, Tohru Tsuda, Isamu Tanaka

Keyword(s):

Gene Expression ◽

Matrix Metalloproteinases ◽

Cigarette Smoke ◽

Secretory Protein ◽

Clara Cell ◽

Clara Cell Secretory Protein ◽

Deficient Mice

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Altered Pulmonary Response to Hyperoxia in Clara Cell Secretory Protein Deficient Mice

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/ajrcmb.17.2.2676 ◽

1997 ◽

Vol 17 (2) ◽

pp. 147-155 ◽

Cited By ~ 112

Author(s):

Carl J. Johnston ◽

Gregory W. Mango ◽

Jacob N. Finkelstein ◽

Barry R. Stripp

Keyword(s):

Secretory Protein ◽

Clara Cell ◽

Pulmonary Response ◽

Clara Cell Secretory Protein ◽

Deficient Mice

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Gene Expression of Matrix Metalloproteinases in Clara-Cell Secretory Protein-Deficient Mice Exposed to Cigarette Smoke

Inhalation Toxicology ◽

10.1080/08958378.2000.11463239 ◽

2000 ◽

Vol 12 (sup3) ◽

pp. 301-305

Author(s):

Yasuo Morimoto ◽

Tohru Tsuda ◽

Isamu Tanaka

Keyword(s):

Gene Expression ◽

Matrix Metalloproteinases ◽

Cigarette Smoke ◽

Secretory Protein ◽

Clara Cell ◽

Clara Cell Secretory Protein ◽

Deficient Mice

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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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