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1 Physiology, Michigan State University, East Lansing, Michigan, United States
2 Service of Pneumology, Hospital Clinic de Barcelona, Barcelona, Spain
3 Physiology, Michigan State University, United States
4 Pathology, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain
5 Medicine, Ministry of Science and Technology, Barcelona, Catalunya, Spain
6 Service of Pneumology, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain
* To whom correspondence should be addressed. E-mail: uhal{at}msu.edu.
Previous work demonstrated de novo synthesis of angiotensin (ANG) peptides by apoptotic alveolar epithelial cells (AEC) and by lung myofibroblasts in vitro and within bleomycin-treated rat. To determine if these cell types also synthesize ANG peptides de novo within the fibrotic human lung in situ, paraffin sections of normal and fibrotic human lung (Idiopathic Pulmonary Fibrosis, IPF) were subjected to immunohistochemistry (IHC) and in situ hybridization (ISH) to detect ANG peptides and angiotensinogen (AGT) mRNA. These were analyzed both alone and in combination with cell-specific markers of AEC (mAB MNF-116) and myofibroblasts (alpha-smooth muscle actin mAB, alpha-SMA) and an in situ DNA end labeling method (ISEL) to detect apoptosis. In normal human lung, IHC detected AGT protein in smooth muscle underlying normal bronchi and vessels, but not elsewhere. Realtime RT-PCR and western blotting revealed that AGT mRNA and protein were 21-fold and 3.6-fold more abundant, respectively, in IPF lung biopsies relative to biopsies of normal human lung (both p<0.05). In IPF lung, both AGT protein and mRNA were detected in AEC that double-labeled with mAB MNF-116 and with ISEL, suggesting AGT expression by apoptotic epithelia in situ. AGT protein and mRNA also colocalized to myofibroblast foci detected by alpha-SMA mAB, but AGT mRNA was not detected in smooth muscle. These data are consistent with earlier data from isolated human lung cells in vitro and with bleomycin-induced rat lung fibrosis models, and suggest that apoptotic AEC and myofibroblasts constitute key sources of locally derived ANG peptides in the IPF lung.
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