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Alfiero Bordigato, Michela (2011) L-citrulline has a protective effect in hyperoxic lung damage and improves matrix remodeling and alveolarization. [Tesi di dottorato]

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Abstract (inglese)

Even moderate hyperoxia alters alveolar and vascular lung morphogenesis. Nitric oxide (NO) and matrix metalloproteinases (MMP) have a crucial role in the homeostasis of the matrix and bronchoalveolar structure, and may be regulated abnormally by exposure to hyperoxia.
We hypothesize that L-citrulline, by raising the serum levels of L-arginine and enhancing endogenous NO synthesis, might attenuate hyperoxia-induced lung injury in an experimental model of bronchopulmonary dysplasia (BPD).
Neonatal rats (1 day old) were exposed to 60% oxygen or room air for 14 days and administered L-citrulline or a vehicle. Serum was tested for arginine level, which rose in the L-citrulline-treated group (p<0.05). Alveolar number decreased in the hyperoxia and vehicle-treated groups, when compared with the room air and L-citrulline treated group (p<0.05). L-citrulline did not affect matrix metalloproteinase2 (MMP2) gene expression, but MMP2 active protein resulted to be higher in bronchoalveolar lavage fluid of the citrulline-treated rats (p<0.05). At the same time, an increased lung VEGF gene expression (p<0.05) and protein immunostaining were also seen in the rats treated with L-citrulline. We conclude that: (i) the main effects of L-citrulline are an increased serum level of arginine, as a promoter and a substrate of the nitric oxide synthase; and (ii) a better alveolar growth and matrix control in hyperoxia-induced lung damage seems promising.

Abstract (italiano)

Nonostante i progressi tecnologici e terapeutici degli ultimi anni, la displasia broncopolmonare (BPD) rimane ancora causa principale di morbilità respiratoria nei neonati prematuri di peso molto basso (VLBW).
L’ossido nitrico (NO) e le metalloproteasi di matrice (MMP) hanno un ruolo cruciale nell’omeostasi della struttura e della matrice broncoalveolare.
In particolare, sempre maggiore è l’evidenza scientifica che attribuisce all’ossido nitrico endogeno un ruolo vitale nello sviluppo alveolare e vascolare del polmone immaturo.
Oltre ad essere un potente vasodilatatore, l’NO ha molti effetti biologici rilevanti: migliora lo scambio gassoso, ha azione antiinfiammatoria e antiossidante, stimola appunto l’angiogenesi e la crescita del polmone immaturo. Il potenziale ruolo di una terapia con NO inalatorio per la prevenzione della BPD è stato recente oggetto di vari studi, ma non è stato ancora chiaramente definito (Horst et al. Am J Physiol Lung Cell Mol Physiol, 2007; Lin et al, Pediatr Res, 2005; McCurnin et al, Am J Physiol Lung Cell Mol Physiol 2005).
L’arginina è il substrato dell’ossido nitrico sintetasi per la produzione di NO. Ci sono evidenze che la supplementazione con L-arginina aumenti la vasodilatazione endotelio-dipendente, mediata dall’NO (Bode-Boger et al, Vasc Med 2003; Piatti et al, Diabetes Care, 2001).
Dopo somministrazione orale però l’arginina è soggetta a un intenso metabolismo presistemico; è stato dimostrato che la supplementazione orale con L-citrullina aumenta significativamente le concentrazioni plasmatiche di arginina, in modo dose dipendente, più che la somministrazione di L-arginina stessa (Kuhn et al. Circulation 2002; Schwedhelm et al. Br J Clin Pharmacol, 2007). Infatti la citrullina viene convertita in arginina sia nelle cellule del tubulo renale prossimale, che in molte cellule in grado di produrre NO (cellule endoteliali e macrofagi), che utilizzano la citrullina come substrato per produrre arginina.


Obiettivi del progetto di ricerca
Scopo di questo progetto era valutare se la somministrazione di L-citrullina, aumentando i livelli plasmatici e/o tissutali di arginina e stimolando la produzione endogena di NO, potesse attenuare il danno polmonare indotto dall’iperossia in un modello sperimentale di BPD.

Materiali e metodi
Ratti neonati wild-type Sprague-Dawley (n=40) sono stati esposti a moderata iperossia moderata (FiO2 60%) per i primi 14 giorni di vita (Man Yi, Am J Respir Crit Care Med, 2004): 12 non hanno ricevuto alcun trattamento, 18 sono stati trattati con L-citrullina 1g/kg/die intraperitoneale, 10 sono stati trattati quotidianamente con placebo (soluzione salina intraperitoneale). Un gruppo di ulteriori 10 ratti sono stati mantenuti in aria ambiente per i primi 14 giorni di vita e utilizzati come controlli. Tutte le procedure sugli animali sono state condotte in maniera conforme al D. L. 116/1992 e secondo autorizzazione n. 173/2006-B del 4.12.2006.
Per valutare l’effetto del trattamento è stata analizzata la morfometria su tessuto polmonare. Ulteriori marker di sviluppo polmonare sono stati analizzati, in particolare VEGF e metalloproteasi 2 (MMP2).

Risultati
Il numero di alveoli /mm2 risultava più basso nei ratti esposti a iperossia e in quelli trattati con placebo rispetto ai ratti cresciuti in aria ambiente e a quelli trattati con L-citrullina (p<0.05).

I livelli sierici di arginina risultavano più elevati nel gruppo trattato con L-citrullina (p<0.05).
Il trattamento con L-citrullina non modificava l’espressione del gene per la metalloproteasi2 (MMP2), ma la proteina attiva MMP2 risultava più elevata nel lavaggio broncoalveolare dei ratti trattati con L-citrullina (p<0.05). Nei ratti trattati con L-citrullina, inoltre, si evidenziava un incremento significativo dell’espressione del gene per il VEGF a livello polmonare (p<0.05).

Conclusioni
La somministrazione di L-citrullina sembra elevare i livelli plasmatici di arginina e potrebbe pertanto promuovere la produzione endogena di NO: il trattamento con citrullina sembra promettente per migliorare la crescita alveolare e il controllo della matrice nel danno polmonare indotto dall’iperossia.

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Tipo di EPrint:Tesi di dottorato
Relatore:Chiandetti, Lino
Dottorato (corsi e scuole):Ciclo 22 > Scuole per il 22simo ciclo > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > GENETICA BIOCHIMICA E MOLECOLARE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:25 Gennaio 2011
Parole chiave (italiano / inglese):nitric oxide, bronchopulmonary dysplasia, L-citrulline
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > Dipartimento di Pediatria
Codice ID:3443
Depositato il:13 Lug 2011 09:28
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