Autonomic reinnervation and functional regeneration in autologous transplanted submandibular glands in patients with severe keratoconjunctivitis sicca
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摘要
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.
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.
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.
引文
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2.Yen,J.C.,Hsu,C.A.,Li,Y.C.&Hsu,M.H.The prevalence of dry eye syndrome’s and the likelihood to develop sjogren’s syndrome in taiwan:a population-based study.Int.J.Environ.Res.Public Health 12,7647-7655(2015).
3.Su,J.Z.,Cai,Z.G.&Yu,G.Y.Microvascular autologous submandibular gland transplantation in severe cases of keratoconjunctivitis sicca.Maxillofac.Plast.Reconstr.Surg.37,5(2015).
4.Sieg,P.et al.Microvascular submandibular gland transfer for severe cases of keratoconjunctivitis sicca.Plast.Reconstr.Surg.106,554-560(2000).
5.Jacobsen,H.C.et al.Long-term results of autologous submandibular gland transfer for the surgical treatment of severe keratoconjunctivitis sicca.J.Craniomaxillofac.Surg.36,227-233(2008).
6.Qin,J.et al.Microvascular autologous transplantation of partial submandibular gland for severe keratoconjunctivitis sicca.Br.J.Ophthalmol.97,1123-1128(2013).
7.Yu,G.Y.et al.Microvascular autologous submandibular gland transfer in severe cases of keratoconjunctivitis sicca.Int.J.Oral.Maxillofac.Surg.33,235-239(2004).
8.Su,J.Z.et al.Effect of computed tomographic venography on donor selection in submandibular gland transplantation in patients with severe dry eye.J.Craniomaxillofac.Surg.45,1692-1697(2017).
9.Borrelli,M.et al.Long-term follow-up after submandibular gland transplantation in severe dry eyes secondary to cicatrizing conjunctivitis.Am.J.Ophthalmol.150,894-904(2010).
10.Geerling,G.,Sieg,P.,Bastian,G.O.&Laqua,H.Transplantation of the autologous submandibular gland for most severe cases of keratoconjunctivitis sicca.Ophthalmology 105,327-335(1998).
11.Liu,X.J.et al.Carbachol improves the secretion of transplanted submandibular glands during the latent period after microvascular autologous transplantation for severe keratoconjunctivitis sicca.Int.J.Oral.Maxillofac.Surg.45,1273-1279(2016).
12.Su,J.Z.et al.Obstructive sialadenitis of a transplanted submandibular gland:chronic inflammation secondary to ductal obstruction.Br.J.Ophthalmol.98,1672-1677(2014).
13.Wang,Y.,Wang,Z.,Yu,G.Y.,Tang,Z.G.&Hu,J.A.Effect of capsaicin cream on the secretion of the submandibular and parotid gland in the general population with different chilli-eating habits.Chin.J.Dent.Res.19,89-93(2016).
14.Su,J.Z.,Liu,X.J.,Zhang,L.&Yu,G.Y.Schirmer test in transplanted submandibular gland:influencing factors and a modified measurement method.Cornea 32,419-422(2013).
15.Knox,S.M.et al.Parasympathetic stimulation improves epithelial organ regeneration.Nat.Commun.4,1494(2013).
16.Geerling,G.et al.Innervation and secretory function of transplanted human submandibular salivary glands.Transplantation 85,135-140(2008).
17.Persson-Sjogren,S.,Forsgren,S.&Taljedal,I.B.Peptides and other neuronal markers in transplanted pancreatic islets.Peptides 21,741-752(2000).
18.Sakamoto,I.et al.Experimental study on hepatic reinnervation after orthotopic liver transplantation in rats.J.Hepatol.37,814-823(2002).
19.Juang,J.H.,Kuo,C.H.,Peng,S.J.&Tang,S.C.3-D imaging reveals participation of donor islet schwann cells and pericytes in islet transplantation and graft neurovascular regeneration.EBio Medicine 2,109-119(2015).
20.Awad,M.et al.Early denervation and later reinnervation of the heart following cardiac transplantation:a review.J.Am.Heart Assoc.5,e004070(2016).
21.Byrne,A.B.et al.Insulin/IGF1 signaling inhibits age-dependent axon regeneration.Neuron 81,561-573(2014).
22.Isomura,E.T.,Yoshitomi,K.,Hamaguchi,M.&Kogo,M.Saliva secretion stimulated by grafted nerve in submandibular gland allograft in dogs.Transplantation 83,759-763(2007).
23.Fox,R.I.&Stern,M.Sjogren’s syndrome:mechanisms of pathogenesis involve interaction of immune and neurosecretory systems.Scand.J.Rheumatol.Suppl.116,3-13(2002).
24.Anderson,L.C.,Garrett,J.R.&Proctor,G.B.Morphological effects of sympathetic nerve stimulation on rat parotid glands 3-4 weeks after the induction of streptozotocin diabetes.Arch.Oral.Biol.35,829-838(1990).
25.Rufini,S.et al.Stevens-Johnson syndrome and toxic epidermal necrolysis:an update on pharmacogenetics studies in drug-induced severe skin reaction.Pharmacogenomics 16,1989-2002(2015).
26.Zhang,S.E.,Su,Y.X.,Zheng,G.S.,Liang,Y.J.&Liao,G.Q.Reinnervated nerves contribute to the secretion function and regeneration of denervated submandibular glands in rabbits.Eur.J.Oral.Sci.122,372-381(2014).
27.Kang,J.H.et al.Parasympathectomy induces morphological changes and alters gene-expression profiles in the rat submandibular gland.Arch.Oral.Biol.55,7-14(2010).
28.Qi,W.et al.Parasympathectomy increases resting salivary secretion in normal and irradiated submandibular glands of rats.Eur.J.Oral.Sci.125,110-118(2017).
29.Ding,C.et al.Hypersensitive m ACh Rs are involved in the epiphora of transplanted glands.J.Dent.Res.93,306-312(2014).
30.Yang,N.Y.et al.Muscarinic acetylcholine receptor-mediated tight junction opening is involved in epiphora in late phase of submandibular gland transplantation.J.Mol.Histol.48,99-111(2017).
31.Ding,C.et al.Decreased interaction between ZO-1 and occludin is involved in alteration of tight junctions in transplanted epiphora submandibular glands.J.Mol.Histol.48,225-234(2017).
32.Dolly,O.Synaptic transmission:inhibition of neurotransmitter release by botulinum toxins.Headache 43(Suppl 1),S16-S24(2003).
33.Kasravi,N.&Jog,M.S.Botulinum toxin in the treatment of lingual movement disorders.Mov.Disord.24,2199-2202(2009).
34.Shan,X.F.,Xu,H.,Cai,Z.G.,Wu,L.L.&Yu,G.Y.Botulinum toxin A inhibits salivary secretion of rabbit submandibular gland.Int.J.Oral.Sci.5,217-223(2013).
35.Xie,S.et al.An experimental study on botulinum toxin type a for the treatment of excessive secretion after submandibular gland transplantation in rabbits.J.Ophthalmol.2016,7058537(2016).
36.Liu,X.J.,Li,M.,Su,J.Z.,Xie,Z.&Yu,G.Y.The timing of acid-induced increase in saliva secretion in transplanted submandibular glands.Int.J.Oral.Maxillofac.Surg.44,1041-1047(2015).
37.Karnovsky,M.J.&Roots,L.A.“direct-coloring”thiocholine method for cholinesterases.J.Histochem.Cytochem.12,219-221(1964).
38.Lopez-Jornet,P.,Camacho-Alonso,F.&Bermejo-Fenoll,A.A simple test for salivary gland hypofunction using Oral Schirmer’s test.J.Oral.Pathol.Med.35,244-248(2006).
2.Yen,J.C.,Hsu,C.A.,Li,Y.C.&Hsu,M.H.The prevalence of dry eye syndrome’s and the likelihood to develop sjogren’s syndrome in taiwan:a population-based study.Int.J.Environ.Res.Public Health 12,7647-7655(2015).
3.Su,J.Z.,Cai,Z.G.&Yu,G.Y.Microvascular autologous submandibular gland transplantation in severe cases of keratoconjunctivitis sicca.Maxillofac.Plast.Reconstr.Surg.37,5(2015).
4.Sieg,P.et al.Microvascular submandibular gland transfer for severe cases of keratoconjunctivitis sicca.Plast.Reconstr.Surg.106,554-560(2000).
5.Jacobsen,H.C.et al.Long-term results of autologous submandibular gland transfer for the surgical treatment of severe keratoconjunctivitis sicca.J.Craniomaxillofac.Surg.36,227-233(2008).
6.Qin,J.et al.Microvascular autologous transplantation of partial submandibular gland for severe keratoconjunctivitis sicca.Br.J.Ophthalmol.97,1123-1128(2013).
7.Yu,G.Y.et al.Microvascular autologous submandibular gland transfer in severe cases of keratoconjunctivitis sicca.Int.J.Oral.Maxillofac.Surg.33,235-239(2004).
8.Su,J.Z.et al.Effect of computed tomographic venography on donor selection in submandibular gland transplantation in patients with severe dry eye.J.Craniomaxillofac.Surg.45,1692-1697(2017).
9.Borrelli,M.et al.Long-term follow-up after submandibular gland transplantation in severe dry eyes secondary to cicatrizing conjunctivitis.Am.J.Ophthalmol.150,894-904(2010).
10.Geerling,G.,Sieg,P.,Bastian,G.O.&Laqua,H.Transplantation of the autologous submandibular gland for most severe cases of keratoconjunctivitis sicca.Ophthalmology 105,327-335(1998).
11.Liu,X.J.et al.Carbachol improves the secretion of transplanted submandibular glands during the latent period after microvascular autologous transplantation for severe keratoconjunctivitis sicca.Int.J.Oral.Maxillofac.Surg.45,1273-1279(2016).
12.Su,J.Z.et al.Obstructive sialadenitis of a transplanted submandibular gland:chronic inflammation secondary to ductal obstruction.Br.J.Ophthalmol.98,1672-1677(2014).
13.Wang,Y.,Wang,Z.,Yu,G.Y.,Tang,Z.G.&Hu,J.A.Effect of capsaicin cream on the secretion of the submandibular and parotid gland in the general population with different chilli-eating habits.Chin.J.Dent.Res.19,89-93(2016).
14.Su,J.Z.,Liu,X.J.,Zhang,L.&Yu,G.Y.Schirmer test in transplanted submandibular gland:influencing factors and a modified measurement method.Cornea 32,419-422(2013).
15.Knox,S.M.et al.Parasympathetic stimulation improves epithelial organ regeneration.Nat.Commun.4,1494(2013).
16.Geerling,G.et al.Innervation and secretory function of transplanted human submandibular salivary glands.Transplantation 85,135-140(2008).
17.Persson-Sjogren,S.,Forsgren,S.&Taljedal,I.B.Peptides and other neuronal markers in transplanted pancreatic islets.Peptides 21,741-752(2000).
18.Sakamoto,I.et al.Experimental study on hepatic reinnervation after orthotopic liver transplantation in rats.J.Hepatol.37,814-823(2002).
19.Juang,J.H.,Kuo,C.H.,Peng,S.J.&Tang,S.C.3-D imaging reveals participation of donor islet schwann cells and pericytes in islet transplantation and graft neurovascular regeneration.EBio Medicine 2,109-119(2015).
20.Awad,M.et al.Early denervation and later reinnervation of the heart following cardiac transplantation:a review.J.Am.Heart Assoc.5,e004070(2016).
21.Byrne,A.B.et al.Insulin/IGF1 signaling inhibits age-dependent axon regeneration.Neuron 81,561-573(2014).
22.Isomura,E.T.,Yoshitomi,K.,Hamaguchi,M.&Kogo,M.Saliva secretion stimulated by grafted nerve in submandibular gland allograft in dogs.Transplantation 83,759-763(2007).
23.Fox,R.I.&Stern,M.Sjogren’s syndrome:mechanisms of pathogenesis involve interaction of immune and neurosecretory systems.Scand.J.Rheumatol.Suppl.116,3-13(2002).
24.Anderson,L.C.,Garrett,J.R.&Proctor,G.B.Morphological effects of sympathetic nerve stimulation on rat parotid glands 3-4 weeks after the induction of streptozotocin diabetes.Arch.Oral.Biol.35,829-838(1990).
25.Rufini,S.et al.Stevens-Johnson syndrome and toxic epidermal necrolysis:an update on pharmacogenetics studies in drug-induced severe skin reaction.Pharmacogenomics 16,1989-2002(2015).
26.Zhang,S.E.,Su,Y.X.,Zheng,G.S.,Liang,Y.J.&Liao,G.Q.Reinnervated nerves contribute to the secretion function and regeneration of denervated submandibular glands in rabbits.Eur.J.Oral.Sci.122,372-381(2014).
27.Kang,J.H.et al.Parasympathectomy induces morphological changes and alters gene-expression profiles in the rat submandibular gland.Arch.Oral.Biol.55,7-14(2010).
28.Qi,W.et al.Parasympathectomy increases resting salivary secretion in normal and irradiated submandibular glands of rats.Eur.J.Oral.Sci.125,110-118(2017).
29.Ding,C.et al.Hypersensitive m ACh Rs are involved in the epiphora of transplanted glands.J.Dent.Res.93,306-312(2014).
30.Yang,N.Y.et al.Muscarinic acetylcholine receptor-mediated tight junction opening is involved in epiphora in late phase of submandibular gland transplantation.J.Mol.Histol.48,99-111(2017).
31.Ding,C.et al.Decreased interaction between ZO-1 and occludin is involved in alteration of tight junctions in transplanted epiphora submandibular glands.J.Mol.Histol.48,225-234(2017).
32.Dolly,O.Synaptic transmission:inhibition of neurotransmitter release by botulinum toxins.Headache 43(Suppl 1),S16-S24(2003).
33.Kasravi,N.&Jog,M.S.Botulinum toxin in the treatment of lingual movement disorders.Mov.Disord.24,2199-2202(2009).
34.Shan,X.F.,Xu,H.,Cai,Z.G.,Wu,L.L.&Yu,G.Y.Botulinum toxin A inhibits salivary secretion of rabbit submandibular gland.Int.J.Oral.Sci.5,217-223(2013).
35.Xie,S.et al.An experimental study on botulinum toxin type a for the treatment of excessive secretion after submandibular gland transplantation in rabbits.J.Ophthalmol.2016,7058537(2016).
36.Liu,X.J.,Li,M.,Su,J.Z.,Xie,Z.&Yu,G.Y.The timing of acid-induced increase in saliva secretion in transplanted submandibular glands.Int.J.Oral.Maxillofac.Surg.44,1041-1047(2015).
37.Karnovsky,M.J.&Roots,L.A.“direct-coloring”thiocholine method for cholinesterases.J.Histochem.Cytochem.12,219-221(1964).
38.Lopez-Jornet,P.,Camacho-Alonso,F.&Bermejo-Fenoll,A.A simple test for salivary gland hypofunction using Oral Schirmer’s test.J.Oral.Pathol.Med.35,244-248(2006).