Autonomic reinnervation and functional regeneration in autologous transplanted submandibular glands in patients with severe keratoconjunctivitis sicca

Xueming Zhang,Liling Wu,Xiaojing Liu,Guangyan Yu,Yan Zhang,Xin Cong,Jiazeng Su,Ningyan Yang

doi:10.1038/s41368-018-0014-1

Abstract

Autologous submandibular gland (SMG) transplantation has been proved to ameliorate the discomforts in patients with severe keratoconjunctivitis sicca. The transplanted glands underwent a hypofunctional period and then restored secretion spontaneously. This study aims to investigate whether autonomic nerves reinnervate the grafts and contribute to the functional recovery, and further determine the origin of these nerves. Parts of the transplanted SMGs were collected from the epiphora patients, and a rabbit SMG transplantation model was established to fulfill the serial observation on the transplanted glands with time. The results showed that autonomic nerves distributed in the transplanted SMGs and parasympathetic ganglionic cells were observed in the stroma of the glands. Low-dense and unevenly distributed cholinergic axons, severe acinar atrophy and fibrosis were visible in the patients’ glands 4–6 months post-transplantation, whereas the cholinergic axon density and acinar area were increased with time. The acinar area or the secretory flow rate of the transplanted glands was statistically correlated with the cholinergic axon density in the rabbit model, respectively. Meanwhile, large cholinergic nerve trunks were found to locate in the temporal fascia lower to the gland, and sympathetic plexus concomitant with the arteries was observed both in the adjacent fascia and in the stroma of the glands. In summary, the transplanted SMGs are reinnervated by autonomic nerves and the cholinergic nerves play a role in the morphological and functional restoration of the glands. Moreover, these autonomic nerves might originate from the auriculotemporal nerve and the sympathetic plexus around the supplying arteries.

Highlights

Keratoconjunctivitis sicca (KCS), known as dry eye syndrome, is one of the leading causes for patients visiting ophthalmologists.[1,2]Microvascular autologous submandibular gland (SMG) transplantation has been proved to be an effective treatment for severe cases of KCS.[3,4,5,6,7,8,9,10] The clinical time-course after SMG transplantation could be divided as follows: (1) 1st–2nd day of transient hypofunctional period; (2) 3rd–6th day of temporary epiphora period; (3) 3 months of latent period; (4) recovery period thereafter.[3]
The cholinergic nerve redistribution, histological change and the secretory function of the glands in the rabbit SMG transplantation model As there were few opportunities to get a series of SMG biopsies from the patients who underwent the transplantation surgery, we established a rabbit SMG transplantation model
Serious gland atrophy and fibrosis were observed at 1 month post-transplantation, whereas the mild restoration of glandular structure occurred at 3 months post-transplantation and the structural restoration further improved at 9 months posttransplantation

Summary

Introduction

Keratoconjunctivitis sicca (KCS), known as dry eye syndrome, is one of the leading causes for patients visiting ophthalmologists.[1,2]. Microvascular autologous submandibular gland (SMG) transplantation has been proved to be an effective treatment for severe cases of KCS.[3,4,5,6,7,8,9,10] The clinical time-course after SMG transplantation could be divided as follows: (1) 1st–2nd day of transient hypofunctional period; (2) 3rd–6th day of temporary epiphora period; (3) 3 months of latent period; (4) recovery period thereafter.[3] The major complications that may cause transplantation failure are vascular crisis in the initial phase and chronic obstructive sialadenitis during the latent period when hyposecretion lasts.[11,12] Administration of capsaicin and carbachol have been introduced to deal with these problems.[11,13] After the latent period, the transplanted glands restore the secretory function spontaneously. In order to find better ways to prevent or treat such complications, the regulatory mechanism of the transplanted glands need to be clarified

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