This proposal will study the effects of lung denervation on the structure and function of the airways by testing two general hypotheses: a.increased airway strain during breathing initiates a fibroproliferative response in denervated airways and b. neurotrophins produced by denervated neuronal targets modify neuropeptide gene expression in airway parasympathetic ganglia. The experimental approach will pursue two specific aim.
The first aim will be to define the effects of denervation on the transciptional regulation of type I procollagen in rats. Accordingly, procollagen expression will be assessed by i situ hybridization after unilateral lung vagotomy or syngeneic lung transplantation. Differences in procollagen mRNA levels between denervated and control lungs will be: 1. examined after experimental manipulations of airway strain and 2. related to the expression of two growth factors which contain strain- responsive elements in their gene promoter and may up-regulate collagen transcription: platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta).
The second aim will be to elucidate the mechanisms that determine the peptidergic phenotype of denervated human and rat airway parasympathetic ganglia. The expressions of protachykinin gene products and their receptors will be studied by in situ hybridization, solution hybridization-nuclease protection assays, and immunohistochemistry in denervated rat lungs and xenografts prepared by implanting rat airways and human bronchi into subcutaneous tissue of immonodeficient mice. The resultant temporal profile of pre-protachykinin and neurokinin receptor expressions will be: 1. related pharmacologically to neurokinin contribution to bronchomotor tone, 2 evaluated after extended neurokinin receptor inhibition, and 3. contrasted to the expression of neurotrophins by denervated airway tissues and neurotrophin receptors by ganglion neurons. The information gained from this research will not only advance the current understanding of the biological function of airway nerves, but will also provide valuable insight into the pathogenesis of lung transplantation-induced bronchiolitis obliterans and other potential airway injuries cause by pharmacological or mechanical disruption of airway smooth muscle tone.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057998-03
Application #
2901292
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Chavolla-Calderon, Mara; Bayer, Meggan K; Fontan, J Julio Perez (2003) Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation. J Clin Invest 111:973-80
Perez Fontan, J J; Velloff, C R (2001) Labeling of vagal motoneurons and central afferents after injection of cholera toxin B into the airway lumen. Am J Physiol Lung Cell Mol Physiol 280:L152-64
Fontan, J J; Diec, C T; Velloff, C R (2000) Bilateral distribution of vagal motor and sensory nerve fibers in the rat's lungs and airways. Am J Physiol Regul Integr Comp Physiol 279:R713-28
Fontan, J J; Cortright, D N; Krause, J E et al. (2000) Substance P and neurokinin-1 receptor expression by intrinsic airway neurons in the rat. Am J Physiol Lung Cell Mol Physiol 278:L344-55
Carver Jr, T W; Srinathan, S K; Velloff, C R et al. (1997) Increased type I procollagen mRNA in airways and pulmonary vessels after vagal denervation in rats. Am J Respir Cell Mol Biol 17:691-701