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161 IS THE BREAKDOWN OF EPITHELIAL-MESENCHYMAL PARACRINE SIGNALING THE CAUSE OF INTERSTITIAL LUNG DISEASE IN SURFACTANT PROTEIN-C DEFICIENCY?
  1. V. K. Rehan,
  2. S. Sugano,
  3. Y. Wang,
  4. J. Santos,
  5. S. W. Glasser,
  6. J. S. Torday
  1. Departments of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, and Cincinnati Children's Hospital Medical Center, OH

Abstract

Background Absence of mature surfactant protein-C (SP-C) has been described in familial interstitial lung disease (ILD). However, the mechanism of ILD associated with the deficiency of SP-C is not known.

Objective To test the hypothesis that SP-C deficiency leads to disruption of parathyroid hormone-related protein (PTHrP)-driven epithelial-mesenchymal interactions that have been previously shown by us to be essential in the maintenance of lung homeostasis (Torday et al, Pediatr Pathol Mol Med, 2003; 22:189-207).

Methods Lungs from 129S6/SvEvTac (129/Sv) SP-C null mice that are known to develop ILD were analyzed for the key markers of alveolar epithelial-mesenchymal interactions at two pathologically distinct, “early” (2 weeks) and “late” (5 months) stages of ILD. The specific markers of epithelial-mesenchymal interactions analyzed included the PTHrP receptor, peroxisome proliferator activated receptor γ (PPARγ), adipocyte differentiation related protein (ADRP), surfactant protein-B (SP-B), and α smooth muscle actin (SMA) expression, by RT-PCR, Western hybridization, and immunohistochemistry.

Results When compared to wild-type controls, the expression of all pro-homeostatic (PTHrP receptor, PPARγ, ADRP, and SP-B (range + 20 60%) alveolar markers increased significantly in early (n = 4, p < .05) but decreased significantly in late (-12-50%) (n = 4, p < .05) stages of ILD. In contrast, the expression of αSMA increased significantly (n = 4, p < .05) in both the early (+15%) and the late (+60%) stages of ILD, with a much more pronounced increase in the late vs early stage of ILD.

Conclusions Our data clearly suggest an association of SP-C deficiency with disruption of epithelial-mesenchymal interactions and provide a plausible mechanism for the pathogenesis of ILD in SP-C deficiency. However, to determine the specificity of SP-C deficiency for the disruption of PTHrP-driven epithelial-mesenchymal interactions, studies targeting specific molecular intermediates of this epithelial-mesenchymal paracrine loop are in progress.

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