Dry eye surface disease: inflammation or osmolarity?

May 1, 2006

Woburn, MA-The chicken-and-egg controversy has swirled for years about what causes what in dry eye syndrome, but the scales are tipping in favor of elevated tear film osmolarity as the cause of dry eye surface disease, based on the latest research.

Woburn, MA-The chicken-and-egg controversy has swirled for years about what causes what in dry eye syndrome, but the scales are tipping in favor of elevated tear film osmolarity as the cause of dry eye surface disease, based on the latest research.

The debate has been seesawing back and forth again recently. The inflammation thesis took hold with the release of the dry eye treatment cyclosporine ophthalmic emulsion (Restasis, Allergan) for ocular surface inflammation, according to Dr. Gilbard.

These investigators studied mice with dry eye and looked at the expression of inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α), matrix metalloproteinase-9 (MMP-9), and the mitogen-activated protein kinase (MAPK) pathways c-jun N-terminal kinase (JNK), extracellular-regulated kinase (ERK), and p38. The animals were treated with systemic scopolamine and exposed to an air draft for 1 week or treated with hypertonic saline drops (500 mOsm) 6 times daily for 2 days.

The authors reported that compared with age-matched controls, the tear fluid concentrations of IL-1β and TNF-α measured by ELISA and MMP-9 by zymography were significantly increased in mice with dry eye treated for 7 days. Detected by reverse transcriptase-polymerase chain reaction, the expression by corneal epithelia of IL-1β, TNF-α, and MMP-9 mRNA was also significantly induced in mice with dry eye treated for 7 days. Western blot testing revealed that phosphorylated JNK1/2, ERK1/2, and p38 were markedly increased in corneal epithelia of these mice. Interestingly, 2-day treatment with hypertonic saline also stimulated IL-1β and MMP-9 proteins in tears and their mRNA in corneal epithelia, as well as activation of JNK1/2, ERK1/2, and p38 signaling pathways in corneal epithelia compared with untreated control mice.

The authors concluded that experimental dry eye and exposure to hypertonic saline increases expression and production of IL-1β, TNF-α, MMP-9, and MAPK signaling pathways in the corneal epithelia, findings that, they believe, "establish a link between the hyperosmolar tear film of dry eye and the induction of ocular surface inflammation in keratoconjunctivitis sicca."

Where the debate began

The story begins in 1940, when Henrik Sjögren, MD, took biopsy specimens from patients with Sjögren's syndrome; after analysis he reported that a force appeared to be pulling water across the ocular surface. The next year, Dr. Von Bahr suggested that tear film osmolarity was a function of rate of tear production and tear film evaporation.

Subsequent observations also suggested that increased tear film osmolarity may be the culprit in dry eye, and by the 1970s, data by Sai Mishima, MD, and later Dr. Gilbard showed that patients with dry eye had elevated tear film osmolarity.

The inflammation theory, i.e., that primary inflammation was the key to the dry eye syndrome, surfaced in the 1940s but was negated by Dr. Sjögren, who showed that patients who had the lacrimal glands removed because of epiphora developed dry eye with surface pathology identical to that seen in Sjögren's syndrome. This thereby ruled out the need to invoke a primary inflammatory disease attack on the ocular surface unrelated to decreased tear production, Dr. Gilbard explained.