Mucin Deficiency Causes Functional and Structural Changes of the Ocular Surface

Abstract

MUC5AC is the most abundant gel-forming mucin in the ocular system. However, the specific function is unknown. In the present study, a Muc5ac knockout (KO) mouse model was subject to various physiological measurements as compared to its wide-type (WT) control. Interestingly, when KO mice were compared to WT mice, the mean tear break up time (TBUT) values were significantly lower and corneal fluorescein staining scores were significantly higher. But the tear volume was not changed. Despite the lack of Muc5ac expression in the conjunctiva of KO mice, Muc5b expression was significantly increased in these mice. Corneal opacification, varying in location and severity, was found in a few KO mice but not in WT mice. The present results suggest a significant difference in the quality, but not the quantity, of tear fluid in the KO mice compared to WT mice. Dry eye disease is multifactorial and therefore further evaluation of the varying components of the tear film, lacrimal unit and corneal structure of these KO mice may help elucidate the role of mucins in dry eye disease. Because Muc5ac knockout mice have clinical features of dry eye, this mouse model will be extremely useful for further studies regarding the pathophysiology of the ocular surface in dry eye in humans.

The Ocular Surface Phenotype ofMuc5acandMuc5bNull Mice

“…Using the same Muc5ac null mice, as well as mice null for Muc5b, we examined the ocular surface for the presence of a dry eye phenotype. Results from our study differed greatly from those reported by Floyd et al, 14 as we found no major ocular surface phenotype in the Muc5ac null mice; in fact, no identifiable ocular surface phenotype was observed, even after exposure to desiccating environmental stress. Moreover, our results showed no ocular surface phenotype present in the Muc5b null mice, either before or following exposure to a dry environment in the controlled environment chamber (CEC).…”

“…A recently published manuscript using the same Muc5ac null mice as those used in this study reported that lack of the major secretory mucin Muc5ac caused significant functional and structural changes to the ocular surface in these mice, creating an ocular surface phenotype similar to that observed in dry eye syndrome. 14 While there are many major discrepancies between our data and those reported by Floyd et al, 14 several findings are consistent between the investigations. Neither study found a change in the aqueous tear volume of Muc5ac null mice compared to that of agematched wild-type control mice.…”

“…To add to this point, the study of Floyd et al 14 and our study found that Muc5ac null mice have a significant increase in Muc5b mRNA expression. However, the converse was not observed, as Muc5ac expression levels remained unchanged in Muc5b null mice.…”

“…The generation of the Muc5ac null mouse has been described previously in detail. 14,15 Briefly, the Muc5ac locus was targeted by insertion of LoxP sites into the 5 0 flanking region and intron 1 in CJ7 embryonic stem cells. Null mice then were produced by mating founder animals with Zp3-Cre transgenic (C57BL/6-Tg(Zp3-cre)93Knw/J) mice and subsequently crossing progeny with C57BL/6J mice.…”

Mucins and Mucus

“…Interestingly, Muc5ac-deficient mice have less lung inflammation and pulmonary edema following ventilator-induced lung injury due to reduced pulmonary neutrophil trafficking (Koeppen et al, 2012). These mice also develop symptoms of dry eye disease consistent with inadequate hydration of or protection of the ocular surface (Floyd et al, 2012). Further work is required in multiple tissues to establish the roles of secreted mucins in normal physiology.…”