Clara cell secretory protein (CC16) as a peripheral blood biomarker of lung injury in ventilated preterm neonates

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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Time and pressure dependence of transvascular Clara cell protein, albumin, and IgG transport during ventilator-induced lung injury in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00283.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. L604-L612 ◽

Cited By ~ 17

Author(s):

Sawako Yoshikawa ◽

Judy A. King ◽

Susan D. Reynolds ◽

Barry R. Stripp ◽

James C. Parker

Keyword(s):

Lung Injury ◽

Molecular Size ◽

Dry Weight ◽

Lavage Fluid ◽

Secretory Protein ◽

Clara Cell ◽

Ultrastructural Changes ◽

Cell Protein ◽

Ventilation Time ◽

Clara Cell Secretory Protein

We compared the transport of three proteins with different hydrodynamic radii with ultrastructural changes in lungs of intact mice ventilated at peak inflation pressures (PIP) of 15, 35, 45, and 55 cmH2O for 2 h and PIP of 55 cmH2O for 0.5 and 1 h. After 2 h of ventilation, significant increases were observed in plasma Clara cell secretory protein (1.9 nm radius) at 35 cmH2O PIP and in bronchoalveolar lavage fluid albumin (3.6 nm radius) at 45 cmH2O PIP and IgG (5.6 nm radius) at 55 cmH2O PIP. Increased concentrations of all three proteins and lung wet-to-dry weight ratios were significantly correlated with PIP and ventilation time. Clara cell secretory protein and albumin increased significantly after 0.5 h of 55 cmH2O PIP, but IgG increased only after 2 h. Separation of endothelium or epithelium to form blebs was apparent only in small vessels (15-30 μm diameter) at 45 cmH2O PIP and after 0.5 h at 55 cmH2O PIP but became extensive after 2 h of ventilation at 55 cmH2O PIP. Junctional gaps between cells were rarely observed. Ultrastructural lung injury and protein clearances across the air-blood barrier were related to ventilation time and PIP levels. Protein clearances increased in relation to molecular size, consistent with increasing dimensions and frequency of transmembrane aqueous pathways.

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The Potential of Lung Epithelium Specific Proteins as Biomarkers for COVID-19-Associated Lung Injury

Diagnostics ◽

10.3390/diagnostics11091643 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1643

Author(s):

Sultan Almuntashiri ◽

Chelsea James ◽

Xiaoyun Wang ◽

Budder Siddiqui ◽

Duo Zhang

Keyword(s):

Lung Injury ◽

Secretory Protein ◽

Clara Cell ◽

World Health ◽

Clara Cell Secretory Protein ◽

Lung Abnormalities ◽

Pulmonary Manifestations ◽

Major Organ ◽

Specific Proteins ◽

Health Organization

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection was first reported in Wuhan, China, and was declared a pandemic by the World Health Organization (WHO) on 20 March 2020. The respiratory system is the major organ system affected by COVID-19. Numerous studies have found lung abnormalities in patients with COVID-19, including shortness of breath, respiratory failure, and acute respiratory distress syndrome. The identification of lung-specific biomarkers that are easily measurable in serum would be valuable for both clinicians and patients with such conditions. This review is focused on the pneumoproteins and their potential to serve as biomarkers for COVID-19-associated lung injury, including Krebs von den Lungen-6 (KL-6), surfactant proteins (SP-A, SP-B, SP-C, SP-D), and Clara cell secretory protein (CC16). The current findings indicate the aforementioned pneumoproteins may reflect the severity of pulmonary manifestations and could serve as potential biomarkers in COVID-19-related lung injury.

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Structure and Regulation of the Murine Clara Cell Secretory Protein Gene

Genomics ◽

10.1006/geno.1994.1123 ◽

1994 ◽

Vol 20 (1) ◽

pp. 27-35 ◽

Cited By ~ 31

Author(s):

Barry R. Stripp ◽

Jacquelyn A. Huffman ◽

Robert J. Bohinski

Keyword(s):

Protein Gene ◽

Secretory Protein ◽

Clara Cell ◽

Clara Cell Secretory Protein

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The Expression of Clara Cell Secretory Protein in BAL Fluid of Patients with Idiopathic Interstitial Pneumonia

Tuberculosis and Respiratory Diseases ◽

10.4046/trd.2002.53.2.127 ◽

2002 ◽

Vol 53 (2) ◽

pp. 127

Author(s):

Sang Won Um ◽

Seon Jin Han ◽

Chang Min Choi ◽

Chang Hoon Lee ◽

Chul Gyu Yoo ◽

...

Keyword(s):

Interstitial Pneumonia ◽

Secretory Protein ◽

Idiopathic Interstitial Pneumonia ◽

Clara Cell ◽

Clara Cell Secretory Protein

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Bone Marrow Clara Cell Secretory Protein-Expressing Cells Rescue Mice with Irreversible Loss of Lung Progenitors.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a2401 ◽

2009 ◽

Author(s):

ML Bustos ◽

AP Wong ◽

TK Waddell

Keyword(s):

Bone Marrow ◽

Secretory Protein ◽

Clara Cell ◽

Irreversible Loss ◽

Clara Cell Secretory Protein ◽

Lung Progenitors

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IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00404.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. L67-L75 ◽

Cited By ~ 27

Author(s):

Suil Kim ◽

Jae Jeong Shim ◽

Pierre-Regis Burgel ◽

Iris F. Ueki ◽

Trang Dao-Pick ◽

...

Keyword(s):

Growth Factor ◽

Protein Expression ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Secretory Protein ◽

Clara Cell ◽

Clara Cell Secretory Protein ◽

Gene And Protein Expression

Previous work showed that the Th2 cytokine interleukin (IL)-13 induces goblet cell metaplasia via an indirect mechanism involving the expression and subsequent activation of epidermal growth factor receptor (EGFR). Because Clara cell secretory protein (CCSP) expression has been reported in cells that express mucins, we examined the effect of IL-13 on CCSP gene and protein expression in pathogen-free rat airways and in pulmonary mucoepidermoid NCI-H292 cells. Intratracheal instillation of IL-13 induced CCSP mRNA in epithelial cells without cilia within 8–16 h, maximal between 24 and 48 h; CCSP immunostaining increased in a time-dependent fashion, maximal at 48 h. The CCSP immunostaining was localized in nongranulated secretory cells and goblet cells and in the lumen. Pretreatment with the selective EGFR tyrosine kinase inhibitor BIBX1522, cyclophosphamide (an inhibitor of bone marrow leukocyte mobilization), or a blocking antibody to IL-8 prevented CCSP staining. Treatment of NCI-H292 cells with the EGFR ligand transforming growth factor-α, but not with IL-13 alone, induced CCSP gene and protein expression. Selective EGFR tyrosine kinase inhibitors, BIBX1522 and AG1478, prevented CCSP expression in NCI-H292 cells, but the platelet-derived growth factor receptor tyrosine kinase inhibitor AG1295 had no effect. These findings indicate that IL-13 induces CCSP expression via an EGFR- and leukocyte-dependent pathway.

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Clara cell secretory protein deficiency increases oxidant stress response in conducting airways

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.275.2.l348 ◽

1998 ◽

Vol 275 (2) ◽

pp. L348-L356 ◽

Cited By ~ 27

Author(s):

Gregory W. Mango ◽

Carl J. Johnston ◽

Susan D. Reynolds ◽

Jacob N. Finkelstein ◽

Charles G. Plopper ◽

...

Keyword(s):

Stress Response ◽

Mrna Expression ◽

Molecular Basis ◽

Oxidant Stress ◽

Secretory Protein ◽

Protective Role ◽

Clara Cell ◽

Clara Cells ◽

Clara Cell Secretory Protein ◽

Oxidant Sensitivity

Little is known about the molecular basis for differential pulmonary oxidant sensitivity observed between genetically disparate members of the same species. We have generated mice that are deficient in Clara cell secretory protein (CCSP −/−) and that exhibit an oxidant-sensitive phenotype. We characterized the kinetics and distribution of altered stress-response [interleukin-6 (IL-6) and metallothionein (MT)] and epithelial cell-specific [cytochrome P-450 2F2 (CYP2F2)] gene expression to further understand the cellular and molecular basis for altered oxidant sensitivity in 129 strain CCSP −/− mice. Increases in IL-6 and MT mRNA abundance were detected by 2 h of exposure to 1 part/million ozone and preceded reductions in Clara cell CYP2F2 mRNA expression. Despite being qualitatively similar, increases in IL-6 and MT mRNA expression were enhanced in CCSP −/− mice with respect to coexposed 129 strain wild-type mice. Increased MT mRNA expression, indicative of the stress response, localized to the airway epithelium, surrounding mesenchyme, and endothelium of blood vessels. These results demonstrate a protective role for Clara cells and their secretions and indicate potential genetic mechanisms that may influence susceptibility to oxidant stress.

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