Increased pulmonary neurotrophin protein expression in idiopathic interstitial pneumonias.
OBJECTIVE
Idiopathic interstitial pneumoniae (IIPs) are characterized by fibroblast proliferation, extracellular matrix deposition and progressive lung function impairment. Because effective therapeutic strategies still remain limited, research has been directed toward the identification of novel targets for additional therapeutic options. The neurotrophins (NTs) nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and NT-3, beside their importance in nervous, endocrine and immune system activities, participate in chronic inflammatory disorders and in repair processes.


METHODS
We have investigated NT and high and low affinity NT receptor expression in IIPs using immunoblots and immunohistochemistry. Fourteen idiopatic pulmonary fibrosis/usual interstitial pneumoniae (IPF/UIP), eight non specific pneumoniae (NSIP) and eight respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) were analyzed.


RESULTS
Immunoblots revealed that NT and high affinity NT receptor proteins were more abundantly expressed in IPF/UIP than NSIP and RB-ILD patients. In RB-ILD, a faint expression of NT-3 and NT receptors were detected. NT and NT receptor immunostaining was detected in interstitial cells from IPF/UIP, NSIP and RB-ILD patients by immunohistochemistry. Fibroblastic foci in IPF/UIP strongly stained for BDNF and its high affinity receptor TrkB and in lesser amount for NGF, NT-3 and their respective high affinity receptors TrkA and TrkC. Furthermore, in fibroblast culture derived from IPF/UIP patients, the proliferation rate of primary culture and clones derived from primary lines was stimulated by BDNF but down regulated by NT-3. In contrast, NGF did not influence IPF/UIP fibroblasts proliferation.


CONCLUSIONS
Our data suggest that that NTs may exert differential activities on lung fibroblasts and may be considered as potential regulatory molecules influencing fibroblast behavior in IPF/UIP patients. Therefore, NTs may play a role in IIPs patho-physiology representing novel potential therapeutic targets.
Ricci
Alberto
A
Dipartimento di Scienze Cardiovascolari e Respiratorie, Università di Roma La Sapienza, Ospedale Sant'Andrea, Via di Grottarossa, 1035-1039 00189 Roma. alberto.ricci@uniroma1.it
Graziano
Paolo
P
Bronzetti
Elena
E
Saltini
Cesare
C
Sciacchitano
Salvatore
S
Cherubini
Emanuela
E
Renzoni
Elisabetta
E
Du Bois
Roland M
RM
Grutters
Jan C
JC
Mariotta
Salvatore
S
D000328:Adult; D000368:Aged; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism*; D017563:Lung Diseases, Interstitial / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000032:analysis / Q000378:metabolism; D009414:Nerve Growth Factors / Q000032:analysis / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000032:analysis / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D020932:Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases