Stromal Inflammatory Cell Infiltration Research Articles

Anti-Inflammatory and Anti-Fibrotic Effects of Human Amniotic Membrane Mesenchymal Stem Cells and Their Potential in Corneal Repair.

Acute ocular chemical burns are ophthalmic emergencies requiring immediate diagnosis and treatment as they may lead to permanent impairment of vision. The clinical manifestations of such burns are produced by exacerbated innate immune response via the infiltration of inflammatory cells and activation of stromal fibroblasts. New therapies are emerging that are dedicated to repair mechanisms that improve the ocular surface after damage; for example, transplantation of stem cells (SC) has been successfully reported for this purpose. The pursuit of easily accessible, noninvasive procedures to obtain SC has led researchers to focus on human tissues such as amniotic membrane. Human amniotic mesenchymal SC (hAM‐MSC) inhibits proinflammatory and fibrotic processes in different diseases. hAM‐MSC expresses low levels of classical MHC‐I and they do not express MHC‐II, making them suitable for regenerative medicine. The aim of this study was to evaluate the effect of intracameral injection of hAM‐MSC on the clinical manifestations, the infiltration of inflammatory cells, and the activation of stromal fibroblasts in a corneal alkali‐burn model. We also determined the in vitro effect of hAM‐MSC conditioned medium (CM) on α‐SMA+ human limbal myofibroblast (HLM) frequency and on release of neutrophil extracellular traps (NETs). Our results show that intracameral hAM‐MSC injection reduces neovascularization, opacity, stromal inflammatory cell infiltrate, and stromal α‐SMA+ cells in our model. Moreover, in in vitro assays, CM from hAM‐MSC decreased the quantity of α‐SMA+ HLM and the release of NETs. These results suggest that intracameral hAM‐MSC injection induces an anti‐inflammatory and anti‐fibrotic environment that promotes corneal wound healing. Stem Cells Translational Medicine 2018;7:906–917

Unilateral Idiopathic Sensory Trigeminal Nerve Paralysis in a Dog

Background: A spayed-female mixed breed dog was presented due to 2 years reduced visual acuity in the left eye. The investigation revealed corneal melanosis, keratoconjunctivis sicca and loss of facial sensation in the same side. The aim of this report is to describe an unilateral idiopathic sensory trigeminal nerve paralysis and keratitis as consequence of corneal innervation loss was established. Unilateral sensory trigeminal nerve paralysis is a very rare lesion in dogs and causes are unclear.Case: A 5-year-old spayed-female mixed breed dog was presented with a history of two years reduced visual acuity in the left eye. The Schirmer tear test values (without use of topical anesthetic) were 11 and 17 mm/min in the left and right eye respectively. Fluorescein tests were negative for both eyes. All postural reactions and spinal reflexes were normal. Cranial nerve evaluation identified symmetrical facial muscles (temporalis, masseter), indicating no muscle atrophy and normal motor nucleus of the fifth nerve. Absent sensation at the upper and lower lips margins, cornea, eyelids (medial and lateral canthi) and sensation in left nasal side were noted. No palpebral reflex was noticed, but there was spontaneous blinking of eyelids, which indicated normal facial nerve function. All other cranial nerve reflexes including menace response, oculocephalic, and gag reflexes were normal. The owner declined further workup, including cerebrospinal fluid analysis and images studies. According to the clinical presentation and neurological findings, presumptive diagnosis of unilateral idiopathic sensory trigeminal nerve paralysis was established. The dog was observed over 18 months without any clinical improvement. The Schirmer tear test showed same values (12 mm/min) and the melanosis remained unchanged.Discussion: Lesions that affected trigeminal nerve, trigeminal ganglion, or trigeminal tract in the pons and medulla caused facial hypoalgesia or analgesia. The causes of trigeminal nerve damage included neoplasia, trauma, fracture of petrous temporal bone and inflammatory polyneuropathies, but the dog present no signals of these diseases. Trigeminal nerve lesions that affected ophthalmic nerve branch will result in loss of corneal sensation and loss of corneal and palpebral reflex as consequence. Paralysis of this branch cause degenerative changes in the cornea, as neurotrophic keratitis that result in edema and epitelial erosion. The Schirmer tear is the standard test to quantify aqueous tear production and the result (11 mm/min) in dog’s left eye is considered early or subclinical keratoconjunctivis sicca (KCS) sign. The pigmentation results from melanocytic cells migration from the limbal or perilimbal tissues. The keratitis can be active when followed by corneal vascularization, stromal inflammatory cell infiltration and granulation tissue formation. The etiology for idiopathic disease is unknown and isolated sensory trigeminal neuropathy have never been described in dogs. There is no definitive treatment and corticosteroid therapy did not appear to alter the course of the disease in dogs with idiopathic trigeminal neuritis therefore supportive treatment is indicated. The paralysis of trigeminal sensory ophthalmic and maxillary branches can result in corneal alterations.

Longitudinal Changes to Tight Junction Expression and Endothelial Cell Integrity in a Mouse Model of Sterile Corneal Inflammation.

We previously reported that applying toll-like receptor (TLR) ligands to an injured cornea induces corneal edema at 24 hours, which subsides by 1 week. We tested the hypotheses that endothelial expression of the tight-junction protein, zonula occludens-1 (ZO-1), would be altered during experimental sterile corneal inflammation and that endothelial cell density (ECD) would remain unaffected. Anesthetized C57BL/6J mice received central 1-mm corneal abrasions followed by topical application of saline or cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN, TLR-9 agonist). At 24 hours, 1 week and 4 weeks post treatment, spectral-domain optical coherence tomography images were captured. Eyes were enucleated and processed for zonula occludens-1 (ZO-1) immunofluorescent staining. Corneal flatmounts were analyzed for endothelial ZO-1 expression, cell density, polymegethism, and polymorphism. Corneal stromal inflammatory cell infiltration was evaluated at 4 weeks by immunostaining for CD45. Central corneal thickness (CCT) was increased in CpG-ODN treated eyes at 24 hours, had normalized by 1 week, but was again thickened by 4 weeks. In eyes with CpG-ODN, endothelial cell ZO-1 expression was reduced at 24 hours but returned to normal levels by 1 week. Endothelial cell density was not altered at 24 hours or 1 week. By 4 weeks, only CpG-ODN eyes showed relatively reduced ECD, as well as large numbers of CD45+ cells in the stroma. Changes to ECD correlated with CCT (r = -0.53, P < 0.01). Compared with naïve controls, more saline- and CpG-ODN-treated eyes exhibited polymegethism. This study provides novel insights into the interplay between endothelial cell integrity, corneal edema, and chronic stromal leukocyte activation during sterile corneal inflammation in mice.

Longitudinal Changes to Tight Junction Expression and Endothelial Cell Integrity in a Mouse Model of Sterile Corneal Inflammation.

PURPOSE: We previously reported that applying toll-like receptor (TLR) ligands to an injured cornea induces corneal edema at 24 hours, which subsides by 1 week. We tested the hypotheses that endothelial expression of the tight-junction protein, zonula occludens-1 (ZO-1), would be altered during experimental sterile corneal inflammation and that endothelial cell density (ECD) would remain unaffected. METHODS: Anesthetized C57BL/6J mice received central 1-mm corneal abrasions followed by topical application of saline or cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN, TLR-9 agonist). At 24 hours, 1 week and 4 weeks post treatment, spectral-domain optical coherence tomography images were captured. Eyes were enucleated and processed for zonula occludens-1 (ZO-1) immunofluorescent staining. Corneal flatmounts were analyzed for endothelial ZO-1 expression, cell density, polymegethism, and polymorphism. Corneal stromal inflammatory cell infiltration was evaluated at 4 weeks by immunostaining for CD45. RESULTS: Central corneal thickness (CCT) was increased in CpG-ODN treated eyes at 24 hours, had normalized by 1 week, but was again thickened by 4 weeks. In eyes with CpG-ODN, endothelial cell ZO-1 expression was reduced at 24 hours but returned to normal levels by 1 week. Endothelial cell density was not altered at 24 hours or 1 week. By 4 weeks, only CpG-ODN eyes showed relatively reduced ECD, as well as large numbers of CD45+ cells in the stroma. Changes to ECD correlated with CCT (r = −0.53, P < 0.01). Compared with naive controls, more saline- and CpG-ODN–treated eyes exhibited polymegethism. CONCLUSIONS: This study provides novel insights into the interplay between endothelial cell integrity, corneal edema, and chronic stromal leukocyte activation during sterile corneal inflammation in mice.

Clinical Significance of Swollen Duodenal Papilla in Autoimmune Pancreatitis

To evaluate the clinical significance of a swollen main duodenal papilla and the associated immunohistopathologic findings in patients with autoimmune pancreatitis (AIP). Seventeen consecutive patients with AIP registered between April 2001 and October 2005 who underwent both endoscopic retrograde cholangiopancreatography and endoscopic biopsy were enrolled in this study. The endoscopic features, stromal inflammatory cell infiltrate (SICI), and results of immunohistochemical examination of the duodenal papilla using IgG4, CD3, and CD79a antibodies were retrospectively reviewed. These findings in the AIP patients were compared with those in 12 patients with chronic alcoholic tumor-forming pancreatitis (CAP). The numbers of cells in the SICI and of IgG4-positive plasma cells per high-power field were counted in all the histopathologic specimens. A swollen main duodenal papilla was observed in 11 (11 [64.7%]/17) patients with AIP and 4 (4 [33.3%]/12) patients with CAP (P < 0.05). Resolution of the swollen main duodenal papilla was observed in all of these 11 patients with AIP (11 [100%]/11) in response to treatment with corticosteroids. On the other hand, the 6 patients without elevated serum IgG4 or a swollen duodenal papilla, but with a swollen pancreas, improved even without corticosteroid treatment. The number of cells in the SICI in the AIP patients was significantly higher than that in the CAP patients. Although in 13 of 17 AIP patients, infiltration by IgG4-positive plasma cells was detected in the duodenal papilla, no such significant infiltration of the duodenal papilla by IgG4-positive plasma cells was observed in the patients with CAP (P < 0.05). More predominant T-cell infiltration of the duodenal papilla was recognized in the AIP patients than in the CAP patients (P < 0.05). These results suggest that a swollen main duodenal papilla with IgG4-positive plasma cell and T-cell-dominant infiltration and an abundant stromal cell infiltrate are characteristic findings in AIP. We suggest that these findings may be valuable adjuncts to the diagnosis of AIP as well as for selecting suitable candidates for corticosteroid therapy.

Histopathologic Features of Conjunctival Filtering Blebs

To characterize and compare the histological features of conjunctiva obtained during the repair of trabeculectomy and inadvertent blebs and to assess the effects of antifibrotic agents. We used routine paraffin processing and light microscopy to examine conjunctival specimens from 28 eyes undergoing late bleb revision: 19 leaking trabeculectomy blebs, 5 nonleaking trabeculectomy blebs, and 4 inadvertent blebs. Quantitative analysis of histological characteristics included conjunctival epithelial thickness, stromal vascularity, squamous metaplasia, stromal inflammatory cell infiltrate, and goblet cell density. The type of surgery, presence of leaks, prior topical medication, and antifibrotic use were correlated with histological findings. Trabeculectomy blebs (leaking and nonleaking) showed decreases in overall epithelial thickness (P<.02), goblet cell density (P<.001), and vascularity (P<.001) compared with inadvertent bleb controls. Conjunctiva exposed to antifibrotics had fewer layers of epithelial cells than those with no prior exposure (P<.05). Histological analysis of thin blebs excised following trabeculectomy demonstrated decreases in epithelial thickness and goblet cell density compared with inadvertent blebs. Both leaking and nonleaking trabeculectomy blebs exhibited decreases in localized stromal vascularity and increases in surrounding stromal vascularity compared with normal conjunctiva.

Surgical pathologic factors that predict recurrence in stage IB and IIA cervical carcinoma patients with negative pelvic lymph nodes

BACKGROUND The purpose of this analysis was to identify pathologic risk factors for recurrence and patterns of recurrence in patients with International Federation of Gynecology and Obstetrics Stage IB and IIA cervical carcinoma and negative pelvic lymph nodes after radical hysterectomy. METHODS During the period 1982-1991, 271 clinically staged patients with Stage IB or IIA cervical carcinoma underwent a Wertheim-Okabayashi radical hysterectomy with pelvic lymph node dissection. The study group was composed of 196 lymph node negative patients. Pathology slides were reviewed and multivariate analysis performed to identify independent prognostic factors. RESULTS The recurrence rate in the study group was 7.7%. In multivariate analysis, the following factors were identified as independent risk factors for recurrence: adenocarcinoma (P = 0.003), depth of invasion as a fraction of tumor penetration of the cervical stroma (P = 0.01), and an extensive stromal inflammatory cell infiltrate (P = 0.04). Based on these factors, the following risk groups were identified: a low risk group (N = 140, 5-year disease free interval [DFI] = 97%) and a high risk group (N = 55, 5-year DFI = 81%). An evaluation of the recurrence patterns for these patients showed a predominance of pelvic recurrences. CONCLUSIONS This study showed that among patients with Stage IB and IIA cervical carcinoma and negative pelvic lymph nodes, a subset with a significant risk for recurrence could be identified. Because the majority of recurrences in the lymph node negative group were pelvic recurrences, the value of adjuvant radiotherapy as a treatment for selected lymph node negative patients should be evaluated in a prospective study. Cancer 1997; 80:1234-40. © 1997 American Cancer Society.

Surgical pathologic factors that predict recurrence in stage IB and IIA cervical carcinoma patients with negative pelvic lymph nodes

The purpose of this analysis was to identify pathologic risk factors for recurrence and patterns of recurrence in patients with International Federation of Gynecology and Obstetrics Stage IB and IIA cervical carcinoma and negative pelvic lymph nodes after radical hysterectomy. During the period 1982-1991, 271 clinically staged patients with Stage IB or IIA cervical carcinoma underwent a Wertheim-Okabayashi radical hysterectomy with pelvic lymph node dissection. The study group was composed of 196 lymph node negative patients. Pathology slides were reviewed and multivariate analysis performed to identify independent prognostic factors. The recurrence rate in the study group was 7.7%. In multivariate analysis, the following factors were identified as independent risk factors for recurrence: adenocarcinoma (P = 0.003), depth of invasion as a fraction of tumor penetration of the cervical stroma (P = 0.01), and an extensive stromal inflammatory cell infiltrate (P = 0.04). Based on these factors, the following risk groups were identified: a low risk group (N = 140, 5-year disease free interval [DFI] = 97%) and a high risk group (N = 55, 5-year DFI = 81%). An evaluation of the recurrence patterns for these patients showed a predominance of pelvic recurrences. This study showed that among patients with Stage IB and IIA cervical carcinoma and negative pelvic lymph nodes, a subset with a significant risk for recurrence could be identified. Because the majority of recurrences in the lymph node negative group were pelvic recurrences, the value of adjuvant radiotherapy as a treatment for selected lymph node negative patients should be evaluated in a prospective study.

A morphological study on the histogenesis of human colorectal hyperplastic polyps

Background & Aims Little is known about the histogenesis of human colorectal hyperplastic polyp, although this polyp is clinically very common. Therefore, the structural features of the polyp and their implications regarding histogenesis were studied. Methods A total of 261 foci were examined using scanning electron-microscopic observation of the isolated crypt and surface structure, NaOH cell maceration and scanning electron microscopy, dissecting microscopy, and standard histological analysis. Results In surface view, each polyp crypt was discretely demarcated as in the normal crypt, suggesting that the crypt epithelium had not replaced the adjoining crypt. Notches at the base and various stages of branching, observed in 21.8% of the isolated crypts, were considered to reflect crypt fission. Several polyps with a single crypt mouth consisting of fissioned multiple crypts suggested polyp origin from a single crypt and growth by fission. Juxtaposition of small polyps and their fusion suggested polycentric origin. Almost all polyps showed increased stromal inflammatory cell infiltration and/or a lymphoid follicle at the base. Conclusions Hyperplastic polyps originate by the apparent fusion of single abnormal crypts within a small region of mucosa. The polyps grow by fission of the crypt and fusion of the polycentrically originated polyps. Chronic inflammation has some relation to this process.

P53 protein expression in breast cancer as related to histopathological characteristics and prognosis

Formalin-fixed, paraffin-embedded biopsies of 193 women with primary breast cancer followed-up for over 10 years were analysed immunohistochemically for the expression of p53 protein. Altogether, 58% (113/193) of the tumors were positive for p53 protein. Over-expression of p53 was associated with the ductal type, high-grade tumors, dense stromal inflammatory cell infiltrate, high S-phase fraction, high mitotic frequency and high values of the nuclear factors. In univariate analysis, intense p53 over-expression predicted a poor outcome, whereas a short recurrence-free survival (RFS) was related to p53 negativity. In axillary lymph-node-negative (ANN) tumors, p53 negativity was related to short RFS, and in axillary lymph-node-positive (ANP) tumors this inverse relationship was statistically significant. In Cox's analysis, p53 protein over-expression had no independent prognostic value comparable with the well-established prognostic factors. However, p53 protein accumulation was an independent indicator of long RFS in the entire cohort, in ANP tumors and in rapidly proliferating tumors. The results indicate a dual role for p53 protein over-expression in breast cancer prognosis. The low survival probability associated with intensively p53-positive tumors is probably related to rapid cancer-cell proliferation, whereas the long RFS of p53-positive tumors might be explained by the development of circulating antibodies to p53 protein. The role of p53 protein in breast cancer is incompletely understood, and the p53 gene should be subjected to detailed analysis of specific mutations.

Noninfected Corneal Ulceration

The pathogenesis of noninfected corneal ulcers consistently relates to persistent or extensive epithelial defects, concomitant with stromal inflammatory cell infiltration and enzymatic degradation of collagen and ground substance. The therapeutic approaches to these disorders may be considered on three levels: (1) determination of etiology and institution of primary therapy; (2) promotion of epithelial healing; and (3) limitation of ulceration and support of repair. The latter two aspects feature pharmacological management and limited surgical modalities, particularly the use of tissue adhesive.

Decision-making in the Therapy of External Eye Disease: Noninfected Corneal Ulcers

Despite diverse and multiple clinical etiologies, the pathogenesis of noninfected corneal ulcers consistently relates to persistent or extensive epithelial defects, concomitant with stromal inflammatory cell infiltration and enzymatic degradation of collagen and ground substance. The therapeutic approaches to these disorders may be considered on three levels: (1) the determination of etiology and initiation of primary therapy; (2) promotion of epithelial healing; and (3) limitation of ulceration and support of repair, the latter aspects currently featuring pharmacologic management and limited surgical modalities, particularly the use of tissue adhesive.

Squamous cell carcinoma of the esophagus. Stromal inflammatory cell infiltration as a prognostic factor.

CancerVolume 14, Issue 5 p. 921-933 ArticleFree Access Squamous cell carcinoma of the esophagus. Stromal inflammatory cell infiltration as a prognostic factor Kiichi Takahashi M.D., Kiichi Takahashi M.D. Surgery Department, Tohoku University Medical School, Sendai, JapanSearch for more papers by this author Kiichi Takahashi M.D., Kiichi Takahashi M.D. Surgery Department, Tohoku University Medical School, Sendai, JapanSearch for more papers by this author First published: September/October 1961 https://doi.org/10.1002/1097-0142(196109/10)14:5<921::AID-CNCR2820140504>3.0.CO;2-ICitations: 25AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume14, Issue5September/October 1961Pages 921-933 ReferencesRelatedInformation