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Impaired reparative processes in particular related to hyaluronan in various cutaneous disorders: a structural analysis
Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cutaneous reparative processes, including wound healing, are highly developed procedures in which a chain of actions occurs to reconstitute the function of the wounded tissue. To prevent a delayed or excessive reparative process it is important to understand how this procedure develops and is maintained. One of the major extracellular matrix components of the skin is the glycosaminoglycan hyaluronan (HA). HA contributes to an extracellular environment, which is permissive for cell motility and proliferation, features that may account for HA’s unique properties observed in scarless foetal wound healing. The molecule is found at high concentration whenever proliferation, regeneration and repair of tissue occur.

The aims of the present studies were to analyse the distribution of HA and to investigate its possible role in various cutaneous conditions associated with an impaired reparative process like in scar tissue formation in healing wounds, changed skin characteristics in diabetes mellitus and proliferating activity in basal cell carcinomas.

Tissue biopsies were obtained from healthy human skin, type-I diabetic skin and various scar tissues. The samples were analysed in the light microscope with a hyaluronan-binding-probe, antibodies for collagen I, III, PCNA and Ki-67. Ultrastructural analyses were performed on the same tissue samples.

In normal skin HA was present mainly in the papillary dermis. In epidermis HA was located in between the keratinocytes in the spinous layer. In the different scar tissues the localization of HA varied, with an HA distribution in mature scar type resembling that in normal skin. In keloids the papillary dermis lacked HA, but the thickened epidermis contained more HA than the other scar types. Ultrastructural studies of keloids revealed an altered collagen structure in the dermal layers, with an abundance of thin collagen fibers in the reticular dermis and thicker collagen fibers in the papillary dermis. Furthermore, the keloids displayed epidermal changes, which involved the basement membrane (BM), exhibiting fewer hemidesmosomes, and an altered shape of desmosomes in the entire enlarged spinous layer. These alterations in epidermis are suggested to influence the hydrodynamic and cell regulatory properties of the wounded skin.

In diabetic patients, a reduced HA staining in the basement membrane zone was seen. The staining intensity of HA correlated to the physical properties of the skin reflected by their grades of limited joint mobility (LJM). Furthermore, the HA staining correlated with serum concentration of the HbA1c.

In basal cell carcinomas (BCC), HA occurred predominantly in the tumour stroma. The distribution was most intense in the highly developed superficial BCC type, and resembled that of the papillary dermis of normal skin. In contrast, in the infiltrative BCC type, the tumour stroma stained weakly in the infiltrative part of the tumour. Moreover, the surrounding dermal layer was deranged and devoid of HA. The findings suggest that the tumour stroma in superficial BCC causes a slow, well-regulated cell growth in which the tumour cells do not substantially disturb the normal skin function. In the infiltrative BCC type, the tumour cells cause a disintegration of the tumour stroma as well as the normal surrounding dermis, which permits further spreading of the tumour. In fact, the behaviour of the infiltrative BCC tumour, growing beyond its boundaries, resembles that of the keloid.

The mapping of the distribution of HA could be a useful tool for prognostic information, for evaluating the degree of progress and for deciding the choice of treatment in various diseases of the skin. In skin malignancies such as BCC it can be used to determine the radicality at the surgical excision of the tumour.

Keywords: Hyaluronan, scar tissue, diabetes mellitus, basal cell carcinoma, skin, wound healing

Place, publisher, year, edition, pages
2004. , 53 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 892
Keyword [en]
hyaluronan, scar tissue, diabetes mellitus, basal cell carcinoma, skin, wound healing
Research subject
Oto-Rhino-Laryngology
Identifiers
URN: urn:nbn:se:umu:diva-276ISBN: 91-7305-652-9 (print)OAI: oai:DiVA.org:umu-276DiVA: diva2:142920
Public defence
2004-05-27, Sal B, Byggnad 1 D, Tandläkarhögskolan, 9 tr, NUS, Umeå, 09:00 (English)
Opponent
Available from: 2004-05-11 Created: 2004-05-11 Last updated: 2009-12-08Bibliographically approved
List of papers
1. The distribution of hyaluronan in human skin and mature, hypertrophic and keloid scars
Open this publication in new window or tab >>The distribution of hyaluronan in human skin and mature, hypertrophic and keloid scars
1994 (English)In: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 47, no 7, 483-489 p.Article in journal (Refereed) Published
Abstract [en]

A hyaluronan-binding protein (HABP) was used to locate the distribution of HA in normal skin and in various types of scar tissue: mature scar tissue, hypertrophic scar tissue and keloids. The study was intended to establish whether or not a deviant HA distribution could explain the different clinical features of these scar tissues. The distribution of HA was found to differ between the various scar tissues. In normal skin an intense HA-staining was observed in the papillary dermis. In mature scar tissue the distribution of HA resembled that of normal uninjured tissue, but the layer of HA was thinner. In hypertrophic scar tissue, HA occurred mainly as a narrow strip in the papillary dermis. Keloid tissue showed the least HA-staining of the papillary layer and resembled that of the bulging reticular dermis. In contrast, the thickened granular and spinous layer of the keloid epidermis exhibited an intense HA-staining. We suggest that the altered distribution and amount of HA in these different scar tissues may contribute to their different clinical characteristics. This histochemical technique for the demonstration of HA in scar tissue could be of use in clinical work to decide on therapeutic strategies.

Identifiers
urn:nbn:se:umu:diva-3987 (URN)10.1016/0007-1226(94)90031-0 (DOI)7524987 (PubMedID)
Available from: 2004-05-11 Created: 2004-05-11 Last updated: 2017-12-14Bibliographically approved
2. Loss of hyaluronan in the basement membrane zone of the skin correlates to the degree of stiff hands in diabetes patients
Open this publication in new window or tab >>Loss of hyaluronan in the basement membrane zone of the skin correlates to the degree of stiff hands in diabetes patients
Show others...
2002 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 82, no 5, 329-334 p.Article in journal (Refereed) Published
Abstract [en]

Glycosaminoglycans are important components of all extracellular matrices. One of the glycosaminoglycans is hyaluronan, which is ubiquitously distributed throughout the connective tissue. Hyaluronan is especially abundant in the skin, in which it is of both structural and functional importance. This study describes the localization and distribution of hyaluronan in the skin of healthy individuals and of 23 patients with insulin-dependent diabetes mellitus and various degrees of limited joint mobility. In normal skin, hyaluronan staining was seen in all layers but most prominently in the papillary dermis and the basement membrane zone. In the skin from diabetic patients with normal or only moderately restricted mobility of the hands (limited joint mobility grades 0 and 1), the distribution of hyaluronan was similar to that of normal skin. In the skin of patients with severe restriction in joint mobility (limited joint mobility grade 2) the staining pattern was significantly different with weak hyaluronan staining in the papillary dermis and the basement membrane zone almost devoid of hyaluronan. Moreover, an increased epidermal thickness in the latter patients was evident as well as a pronounced hyaluronan staining compared with normal epidermis.

Keyword
diabetes, hyaluronan, skin, limited joint mobility
Identifiers
urn:nbn:se:umu:diva-3988 (URN)10.1080/000155502320624041 (DOI)12430730 (PubMedID)
Available from: 2004-05-11 Created: 2004-05-11 Last updated: 2017-12-14Bibliographically approved
3. The stromal reaction in basal cell carcinomas: A prerequisite for tumour progression and treatment strategy
Open this publication in new window or tab >>The stromal reaction in basal cell carcinomas: A prerequisite for tumour progression and treatment strategy
2004 (English)In: British Journal of Plastic Surgery, ISSN 0007-1226, E-ISSN 1465-3087, Vol. 57, no 5, 429-439 p.Article in journal (Refereed) Published
Abstract [en]

Specimens of basal cell carcinomas collected from 28 patients were classified into three groups: superficial, nodular, and infiltrative, according to their microarchitecture. The specimens were then subjected to histological characterization by means of a biotinylated hyaluronan-binding probe (HABP). By using Ki-67 and PCNA the proliferative activity of the BCC tumours was evaluated with immunohistological techniques. In superficial BCC the tumour islands displayed moderate hyaluronan (HA) staining. Feeble proliferation, denoted by modest mitotic activity and weak Ki-67 and PCNA immunoreactivity, occurred within the tumour islands. The surrounding connective tissue resembled normal skin, and no differentiated tumour stroma was observed. In nodular BCC, the HA staining of the tumour strands was weak to moderate, denoting increased proliferative activity. The differentiated surrounding tumour stroma stained strongly for HA. Tumour islands of infiltrative BCC stained weakly to moderately to HA and evidenced intense proliferation. The intensely HA-stained tumour stroma ended abruptly and the adjacent areas were almost devoid of HA. This study showed that the proliferative activity of BCC cells is associated with increased expression of HA in the tumour stroma. Modification of tumour-associated connective tissue indicates a close relationship between the tumour cells and the adjacent matrix. In particular, in infiltrative BCC, such alterations include degeneration and possible modification and remodelling of the surrounding extracellular matrix. These processes involving areas of probable importance for tumour progression, should be considered when deciding the extent of intended surgical resection.

Keyword
Carcinoma; Basal Cell/*pathology, Cell Division, Disease Progression, Humans, Immunohistochemistry/methods, Ki-67 Antigen/metabolism, Proliferating Cell Nuclear Antigen/metabolism, Skin Neoplasms/*pathology
Identifiers
urn:nbn:se:umu:diva-7784 (URN)10.1016/j.bjps.2003.12.024 (DOI)15191824 (PubMedID)
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2017-12-14Bibliographically approved
4. Structural changes correlated to hyaluronan are associated with an excessive collagen formation in keloids
Open this publication in new window or tab >>Structural changes correlated to hyaluronan are associated with an excessive collagen formation in keloids
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3990 (URN)
Available from: 2004-05-11 Created: 2004-05-11 Last updated: 2012-05-15Bibliographically approved

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