Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars

Niessen, Frank B.; Andriessen, M.P.M.; Schalkwijk, Joost; Visser, Lydia; Timens, Wim

doi:10.1002/path.853

Cited by 127 publications

(96 citation statements)

References 69 publications

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“…Approximately 15% of subjects who have had pustules biopsied develop hypertrophic scars, demonstrating that an environment that favors excessive collagen synthesis occurs in pustules. TGF-␤ promotes synthesis of procollagen by fibroblasts and is thought to be important in the pathogenesis of hypertrophic scar formation (54), and TGF-␤ mRNA is readily amplified from pustules (unpublished data). Immunohistochemistry and flow cytometry reveal that FOXP3-expressing regulatory CD4 cells are also abundant in pustules of persons infected once (unpublished).…”

Section: Discussionmentioning

confidence: 97%

Dysregulated Immune Profiles for Skin and Dendritic Cells Are Associated with Increased Host Susceptibility toHaemophilus ducreyiInfection in Human Volunteers

Humphreys¹,

Li²,

et al. 2007

Infect Immun

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In experimentally infected human volunteers, the cutaneous immune response to Haemophilus ducreyi is orchestrated by serum, polymorphonuclear leukocytes, macrophages, T cells, and myeloid dendritic cells (DC). This response either leads to spontaneous resolution of infection or progresses to pustule formation, which is associated with the failure of phagocytes to ingest the organism and the presence of Th1 and regulatory T cells. In volunteers who are challenged twice, some subjects form at least one pustule twice (PP group), while others have all inoculated sites resolve twice (RR group). Here, we infected PP and RR subjects with H. ducreyi and used microarrays to profile gene expression in infected and wounded skin. The PP and RR groups shared a core response to H. ducreyi. Additional transcripts that signified effective immune function were differentially expressed in RR infected sites, while those that signified a hyperinflammatory, dysregulated response were differentially expressed in PP infected sites. To examine whether DC drove these responses, we profiled gene expression in H. ducreyi-infected and uninfected monocyte-derived DC. Both groups had a common response that was typical of a type 1 DC (DC1) response. RR DC exclusively expressed many additional transcripts indicative of DC1. PP DC exclusively expressed differentially regulated transcripts characteristic of DC1 and regulatory DC. The data suggest that DC from the PP and RR groups respond differentially to H. ducreyi. PP DC may promote a dysregulated T-cell response that contributes to phagocytic failure, while RR DC may promote a Th1 response that facilitates bacterial clearance.

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Section: Discussionmentioning

confidence: 97%

Dysregulated Immune Profiles for Skin and Dendritic Cells Are Associated with Increased Host Susceptibility toHaemophilus ducreyiInfection in Human Volunteers

Humphreys¹,

Li²,

et al. 2007

Infect Immun

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“…On the other hand, augmented PDGF production might be involved in the pathogenesis of hypertrophic scars and keloids as suggested by the potent effect of PDGF on fibroblast proliferation and extracellular matrix production by these cells (see above), the presence of enhanced levels of this growth factor in hypertrophic scar tissue (198), and the increased responsiveness of keloid fibroblasts to PDGF (114).…”

Section: A Expression Of Pdgf At the Wound Sitementioning

confidence: 99%

Regulation of Wound Healing by Growth Factors and Cytokines

Werner

Grose

2003

Physiological Reviews

3,013

2,082

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Werner, Sabine, and Richard Grose. Regulation of Wound Healing by Growth Factors and Cytokines. Physiol Rev 83: 835–870, 2003; 10.1152/physrev.00032.2002.—Cutaneous wound healing is a complex process involving blood clotting, inflammation, new tissue formation, and finally tissue remodeling. It is well described at the histological level, but the genes that regulate skin repair have only partially been identified. Many experimental and clinical studies have demonstrated varied, but in most cases beneficial, effects of exogenous growth factors on the healing process. However, the roles played by endogenous growth factors have remained largely unclear. Initial approaches at addressing this question focused on the expression analysis of various growth factors, cytokines, and their receptors in different wound models, with first functional data being obtained by applying neutralizing antibodies to wounds. During the past few years, the availability of genetically modified mice has allowed elucidation of the function of various genes in the healing process, and these studies have shed light onto the role of growth factors, cytokines, and their downstream effectors in wound repair. This review summarizes the results of expression studies that have been performed in rodents, pigs, and humans to localize growth factors and their receptors in skin wounds. Most importantly, we also report on genetic studies addressing the functions of endogenous growth factors in the wound repair process.

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“…This rate is much higher than the incidence in the general population (2), considering the ethnic and racial composition of the volunteers. Hypertrophic scar formation is associated with excessive TGF-␤ production (27,46). We postulate that H. ducreyi causes a tolerizing response that promotes phagocytic failure in pustule formers and a proinflammatory response that promotes clearance in resolvers.…”

Section: Downloaded Frommentioning

confidence: 98%

Differences in Host Susceptibility to Disease Progression in the Human Challenge Model ofHaemophilus ducreyiInfection

Spinola

Bong²,

Faber

et al. 2003

Infect Immun

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With human volunteers inoculated at two sites with Haemophilus ducreyi, outcomes for a subject were not independent. In a reinfection trial, 2 of 11 previous pustule formers and 6 of 10 previous resolvers resolved all sites of infection. There was no correlation between serum bactericidal or phagocytic activity and outcome in the trial. These data indicate that different hosts are differentially susceptible to disease progression versus resolution in the model.Human inoculation experiments with many infectious agents have contributed to our understanding of transmission, pathogenesis, natural history, treatment, and vaccine development (12,25,31). After inoculation, some subjects may develop disease while others are asymptomatic or recover without treatment. Reinfection experiments usually have addressed whether experimental or natural infection with a pathogen affords protection against subsequent experimental challenge (5, 14,17,24,33). Reinfection trials generally have not addressed the issue of differences in host susceptibility to disease.To study Haemophilus ducreyi pathogenesis in humans, we developed an experimental model of infection in human volunteers (40). In the model, subjects are inoculated at multiple sites with strain 35000HP (HP, human passaged) via puncture wounds made in the skin of the upper arm by an allergy-testing device (6, 39). Within 24 h of inoculation, papules develop. These spontaneously resolve or progress to pustules in resemblance to the initial stages of natural chancroid. Lesion outcomes for an individual subject inoculated at multiple sites with identical suspensions of 35000HP sometimes differ in that a pustule may develop at one site while another site resolves (6, 39). Due to the fact that outcomes at different sites are not always the same, we initially used site as the unit of measurement for the calculation of papule and pustule formation rates. These analyses show a significant effect of the estimated delivered dose (EDD) on papule and pustule formation rates (4, 10). Although there is no effect of gender on papule formation, men are twice as likely to form pustules as women (consistent with the high male-to-female ratio in natural disease) (10).Throughout experimental infection, H. ducreyi colocalizes with collagen and fibrin and professional phagocytes (7,8). Fibrin and collagen deposition occur as part of the normal process of wound repair and provide a matrix for the infiltrating polymorphonuclear leukocytes (PMNs) and macrophages (7). The presence of fibrin suggests that serum transudates into the wounds. Interestingly, an isogenic mutant that lacks DsrA, an outer membrane protein which has several functions (including serum resistance) (13, 15), forms papules that do not progress to pustule formation (11). In pustules, the parent 35000HP strain is surrounded but not taken up by PMNs or macrophages. Thus, serum resistance and evasion of phagocytosis are virulence determinants in the model.In the model, some subjects form at least one pustule and other subjects reso...

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Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars

Cited by 127 publications

References 69 publications

Dysregulated Immune Profiles for Skin and Dendritic Cells Are Associated with Increased Host Susceptibility toHaemophilus ducreyiInfection in Human Volunteers

Dysregulated Immune Profiles for Skin and Dendritic Cells Are Associated with Increased Host Susceptibility toHaemophilus ducreyiInfection in Human Volunteers

Regulation of Wound Healing by Growth Factors and Cytokines

Differences in Host Susceptibility to Disease Progression in the Human Challenge Model ofHaemophilus ducreyiInfection

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