UTP and diadenosine tetraphosphate accelerate wound healing in the rabbit cornea

Abstract

Nucleotides are naturally occurring substances present in tear film that can stimulate tear secretion in animals and humans. We investigated whether certain nucleotides can affect the rate of wound healing in the cornea of white rabbits. In the absence of any added compound, the rate of healing was 72.4 +/- 2.2 microm h(-1). Of all the tested nucleotides, UTP and Ap(4)A were the most active ones, maximally increasing the rate of healing to 121.6 +/- 3.7 and 93.7 +/- 3.2 microm h(-1), respectively. Responses to UTP were dose dependent. UTP had a pD(2) value of 8.9 +/- 0.1 (EC(50): 1.25 nM). P2 purinoceptor antagonists such as suramin and reactive blue-2, inhibited the effect of UTP indicating the involvement of P2Y receptors. Mitogen-activated protein kinase (MAPK) cascade inhibitors also abolished the effects of UTP, suggesting that P2Y receptors are coupled to the MAPK cascade, and that this is involved in controlling the rate of epithelial cell migration.

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

“…Nucleotides may be released from cells via physical injury, pores in channels, or exocytotic release upon ligand binding causing a rapid elevation in intracellular Ca 2+ (Burnstock 1997;Abbracchio and Burnstock, 1998;Neary et al,1999;Schwiebert and Zsembery, 2003;Yang et al, 2004;Klepeis et al, 2001;Klepeis et al, 2004;Weinger et al, 2005;Pintor et al, 2004). The extracellular nucleotides stimulate cells by activation of P2 purinergic receptors present on the cell surface.…”

The role of dinucleoside polyphosphates on the ocular surface and other eye structures

“…They found that INS-365, aka Up 4 U and also termed diquafosol (see section 2.1.7), has the ability to evoke mucin secretion on In vivo conjunctivas of a rat dry eye model. In 2004 they corroborated their results in the New Zealand white rabbit model (Pintor et al, 2004a). They concluded that INS365 restored moisture and hydration of the ocular surface of rats by its effects on tear and mucin secretion.…”

“…Among natural substances, nucleotides and dinucleotides present in tears have been shown to be very active to modify the rate of healing (Bowman and Green, 1981;Pintor et al, 2004a). Experiments performed in our laboratory on an animal model, demonstrated that the levels of Ap 4 A and Ap 5 A are significantly reduced after the damage, recovering after 10 h. The same ratio of Ap 4 A/Ap 5 A concentration in tears remained stable.…”

“…The presence of diadenosine polyphosphates in the tear film was studied due to their properties to enhance both tear secretion and to increase the wound healing rate (Guzman-Aranguez et al, 2007, 2011Pintor et al, 2004a;Pintor et al, 2002b). The exogenous addition of these dinucleotides suggested their presence as natural constituents of tears.…”

“…Pintor et al found that the estimated healing time was for saline, Ap 3 A, Ap 4 A and Ap 5 A were 32.2 ± 2.0 h, 35 ± 2.6 h, 26.0 ± 0.6 h and 29.2 ± 2.2 h, respectively. It means that only diadenosine tetraphosphate provokes an increase in the wound healing rate (Pintor et al, 2004a). Based on these results, Mediero et al evaluated the role of diadenosine polyphosphate in the epithelial cell migration, performed in primary corneal epithelial cell culture (Mediero et al, 2006).…”