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Budesonide effects on Clara cell under normal and allergic inflammatory condition

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Abstract

Clara cells are nonciliated secretory cells implicated in lung homeostasis by the synthesis of immunomodulatory and host defense products, being one of the most important the CC16 protein. In this study, we compared the effects of budesonide (BUD), an inhaled corticoid, on Clara cell biology and its ability to reverse morphofunctional changes induced in an allergic airway hyper-responsiveness mouse model. In normal mice, exposure to BUD induced morphological changes compatible with a state of maximal differentiation on CC16 positive cells which developed a prominent cupola filled up with numerous mitochondria rich in CYP2E1, a member of the cytochrome P450 family. Consequently, CYP2E1 expression raised significantly. Exposure to OVA provoked hypertrophy of Clara cells and an increment in their number per millimeter of basal membrane. These cells acquired a mucous cell phenotype characterized by a notorious expansion of the secretory granular content. Synthesis of CC16 was greatly up-regulated concurrent to the finding of MUC5AC expression and the increment of epidermal growth factor receptor (EGFR). Mitochondrial content decreased significantly with a consequent reduction in CYP2E1 expression. After BUD treatment of OVA-challenged animals, the majority of Clara cells regained their normal morphology and functional characteristics; CYP2E1 levels raised when compared to the OVA exposed group. The BUD potential to differentiate Clara cells appeared to be important for the regression of the profound changes generated by the allergic injury. These results demonstrated the wide range of stimuli that can modify different aspects of Clara cell biology, and highlighted the effects of budesonide as a modulator of P450 enzymes, which probably contributes to a complementary antiinflamatory activity.

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Abbreviations

BUD:

Budesonide

EGFR:

Epidermal growth factor receptor

CC16:

Clara cell protein

PLA-2:

Phospholipase A-2

Th2:

Lymphocytes T helper 2

OVA:

Ovoalbumin

CYP:

Cytochrome P450

MUC5AC:

Mucin 5AC

TGFβ1 :

Transforming growth factor beta 1

BAL:

Bronchoalveolar lavage

SP:

Surfactant protein

TNFα:

Tumor necrosis factor alpha

IFNγ:

Interferon gamma

EETs:

Epoxyeicosatrienoic acids

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Acknowledgments

The authors thank Mrs. Mercedes Guevara and Elena Pereyra for their technical assistance, Engineer Gabriel Balabanian for his valuable assistance in the use of the electron microscope, and Dr. Jan Ryerse from The University of Saint Louis, USA, for kindly providing the antiserum against CC16. We are particularly indebted to Dr. Jorge Mukdsi for his valuable help in the histopathological descriptions. This study was supported by Grant PEI 1923/03 from the Consejo National de Investigaciones Científicas y Tecnológicas (CONICET) and Grant PICT from FONCyT-ANPCyT.

AA, CM and AT are members of the scientific career from CONICET.

FR and AQ are fellows from FONCyT-ANPCyT and CONICET, respectively.

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Authors and Affiliations

  1. Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Pabellón de Biología Celular, Haya de la Torre y Enrique Barros, 5000, Córdoba, Argentina

    Felix Daniel Roth, Amado Alfredo Quintar, Elisa M. Uribe Echevarría, Alicia Inés Torres, Agustín Aoki & Cristina Alicia Maldonado

  2. Instituto de Fisiopatología Torácica, Hospital Italiano de Córdoba, Córdoba, Argentina

    Elisa M. Uribe Echevarría

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  1. Felix Daniel Roth
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  2. Amado Alfredo Quintar
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  6. Cristina Alicia Maldonado
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Correspondence to Cristina Alicia Maldonado.

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Roth, F.D., Quintar, A.A., Uribe Echevarría, E.M. et al. Budesonide effects on Clara cell under normal and allergic inflammatory condition. Histochem Cell Biol 127, 55–68 (2007). https://doi.org/10.1007/s00418-006-0220-3

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