Hyaluronan in Diseased Ocular Surface Tissues

The eyes of patients suffering from ocular surface disease such as dry eye are characterized by a deterioration of the corneal epithelium with a development of punctate erosions and increased permeability. Compared with normal eyes, the conjunctiva of such patients presents squamous metaplasia with decreased or abnormal goblet cells. In addition, HA and its receptor CD44 modify their pattern of distribution within the ocular surface structures.

It was shown that HA and its receptor CD44 were preferentially located in regions of active cell growth such as in the basal layers of the stratified epithelium (41). In an experimental model on rabbit of corneal epithelial wound healing after exposure to n-heptanol, it was shown that the HA concentration increased gradually in the epithelium starting from day 3, when the epithelium had completely covered the defect, until day 28 after wounding, when the thickness of the epithelium returned to the normal level. Furthermore, in the stroma, HA staining increased after 3 days and returned to normal levels after 56 days. The immunostaining for CD44 and fibronectin paralleled that of HA, suggesting that HA, CD44 and fibronectin cooperatively play a role in wound healing (48).

HA is also involved in the wound healing process which follows excimer laser treatment of the cornea for both refractive and therapeutic purposes. Its presence was found in the subepithelial layer of the stroma up to 44 months after the treatment, despite topical steroid treatment (49-51). HA was visualized in the anterior stroma of the excimer-treated eyes starting from 1 day after the procedure and lasting up to 60 days. Its amount was statistically significantly larger than baseline values starting from day 8 after treatment (52). Furthermore, HA in wound scrapings from human corneas with myopic regression after photorefractive keratectomy (PRK) has been associated with severe haze (53). Steroids have been claimed to reduce the HA content of corneas after PRK (54).

Table 3 Presence of HA in Normal Ocular Surface Structure

Preocular tear film

Table 3 Presence of HA in Normal Ocular Surface Structure

Preocular tear film

Lacrimal tissue

Basal membrane of acinar cells

Ductal cells


Epithelial basal cells

Epithelial basement membrane



Surface of the superficial epithelial cells

Epithelial basal cells (peripheral cornea)

Bowman's layer (peripheral cornea)


Endothelial cells (both peripheral and central cornea)

In some late myopic regression, it was demonstrated that topical steroids were able to restore up to 3 diopters refraction within 1 week of treatment (55). The rapid hyperopic restitution suggested that a water displacement in the wound area could play a role in such a result. HA has been shown to have a strict association with subepithelial water accumulation in corneas after PRK (56). HA seems, therefore, to play an important role in wound healing modulation after excimer laser treatment of the cornea. The endogenous production of HA can also be considered a marker for wound healing reactivity (57).

Reverse transcription-polymerase chain reaction was used to evaluate the expression and distribution of CD44 in the healing corneal epithelium of rat. This study indicated that CD44 transcripts started to increase in the epithelial cells surrounding the wound margin 3 h after wounding and peaked at 18 h in the basal epithelial cell layer, at which time the epithelia were actively migrating. As the cells began proliferation after wounding, the density of CD44 mRNA label declined but was still significantly higher than that in control specimens. The label returned to basal level as epithelial cells reverted to their normal phenotype. Eighteen hours after wounding, CD44 immunoreactivity was elevated in the entire epithelium, from the leading edge to the limbal-corneal border. As happened for the mRNA, the cell surface CD44 declined as cells differentiated to re-establish the multilayered epithelium (58).

Another study, using immunohistochemical method with monoclonal antibodies against human CD44, showed that in normal corneas CD44 was expressed on the membranes of basal epithelial cells and on keratocytes. Enhanced expression was observed on the epithelium of corneas with inflammation and allograft rejection. The authors concluded that CD44, the HA receptor, may play an important role in corneal cell-cell and cell-matrix interactions. Its regulation is closely related to corneal inflammatory reaction (59).

According to the results of these studies, it appears that HA and its receptor CD44 are over-expressed by corneal epithelium in the course of wound healing, suggesting a role of these molecules in the reparative processes of the ocular surface.

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