[Monogenic auto-inflammatory diseases associated with actinopathies: A review of the literature]. / Revue de la littérature sur les syndromes auto-inflammatoires monogéniques liés aux actinopathies.

Auto-inflammatory diseases (AIDs) are diseases resulting from an inappropriate activation of innate immunity in the absence of any infection. The field of monogenic AIDs is constantly expanding, with the discovery of new pathologies and pathophysiological mechanisms thanks to pangenomic sequencing. Actinopathies with auto-inflammatory manifestations are a new emerging group of AIDs, linked to defects in the regulation of the actin cytoskeleton dynamics. These diseases most often begin in the neonatal period and combine to varying degrees a more or less severe primary immune deficiency, cytopenias (especially thrombocytopenia), auto-inflammatory manifestations (especially cutaneous and digestive), atopic and auto-immune manifestations. The diagnosis is to be evoked essentially in front of a cutaneous-digestive auto-inflammation picture of early onset, associated with a primary immune deficiency and thrombocytopenia or a tendency to bleed. Some of these diseases have specificities, including a risk of macrophagic activation syndrome or a tendency to atopy or lymphoproliferation. We propose here a review of the literature on these new diseases, with a proposal for a practical approach according to the main associated biological abnormalities and some clinical particularities. However, the diagnosis remains genetic, and several differential diagnoses must be considered. The pathophysiology of these diseases is not yet fully elucidated, and studies are needed to better clarify the inherent mechanisms that can guide the choice of therapies. In most cases, the severity of the picture indicates allogeneic marrow transplantation.

[Myelofibrosis: A review]. / Les myélofibroses.

Myelofibrosis is a BCR-ABL1-negative chronic myeloproliferative neoplasm that includes primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. It is characterized by stem cell-derived clonal proliferation that is often, but not always, accompanied by somatic mutations, which are classified into driver mutations (JAK2, CALR, or MPL), subclonal mutations and fibrosis on bone marrow biopsy. Myelofibrosis commonly demonstrates splenomegaly, constitutional symptoms, anemia, thrombocytosis, or thrombocytopenia. Patients may also be asymptomatic. Complications as thromboembolic or hemorrhagic events can reveal the disease. Primary myelofibrosis is the least common myeloproliferative neoplasm but is associated with poor survival and acute leukemic transformation. In contrast to the significant progress made in understanding the disease's pathogenesis, treatment for myelofibrosis remains largely palliative. The JAK2 inhibitor, ruxolitinib is not sufficient in eliminating the underlying myeloid progenitor clone, as disease inevitably returns with therapy discontinuation. Allogeneic hematopoietic stem cell transplantation is the only therapeutic option that offers potential cure. The development of novel treatment strategies aimed at slowing or even reversing disease progression, prolonging patient survival and preventing evolution to blast-phase are still lacking.

An octyl-2-cyanoacrylate formulation speeds healing of partial-thickness wounds.

BACKGROUND: Occlusive dressings have been known to accelerate the rate of healing. Every year new dressings are being introduced in the marketplace. OBJECTIVE: The purpose of this study was to evaluate the effect of a new octyl-2-cyanoacrylate liquid dressing as compared to two over-the-counter bandages on partial-thickness wounds. Performance parameters were epithelialization, erythema, scab formation, material adherence, hemostasis, and infection. METHOD: Eight pigs with a total of 645 partial-thickness wounds were assigned to one of the following treatments: liquid dressing, standard bandage, hydrocolloid bandage, or untreated air exposed. RESULT: The liquid bandage enhanced the rate of epithelialization and was the only treatment to provide complete hemostasis, reduced scab formation, and did not induce an irritant response (erythema) or infection. CONCLUSION: The liquid bandage is an easy to use material that stops bleeding (instantaneous hemostasis) while enhancing healing of partial-thickness wounds.

The pig as a model for human wound healing.

The medical literature describes numerous in vitro and in vivo wound-healing models. The selection of an animal model depends on a number of factors including availability, cost, ease of handling, investigator familiarity, and anatomical/functional similarity to humans. Small mammals are frequently used for wound healing studies, however, these mammals differ from humans in a number of anatomical and physiological ways. Anatomically and physiologically, pig skin is more similar to human skin. The many similarities between man and pig would lead one to believe that the pig should make an excellent animal model for human wound healing. The purpose of this paper is to review the existing literature for evidence of this supposition and determine how well the various models correlate to human wound healing. Studies of wound dressings, topical antimicrobials, and growth factors are examined. Over 180 articles were utilized for this comparative review. Our conclusion is that the porcine model is an excellent tool for the evaluation of therapeutic agents destined for use in human wounds.

Calcineurin: form and function.

Calcineurin is a eukaryotic Ca(2+)- and calmodulin-dependent serine/threonine protein phosphatase. It is a heterodimeric protein consisting of a catalytic subunit calcineurin A, which contains an active site dinuclear metal center, and a tightly associated, myristoylated, Ca(2+)-binding subunit, calcineurin B. The primary sequence of both subunits and heterodimeric quaternary structure is highly conserved from yeast to mammals. As a serine/threonine protein phosphatase, calcineurin participates in a number of cellular processes and Ca(2+)-dependent signal transduction pathways. Calcineurin is potently inhibited by immunosuppressant drugs, cyclosporin A and FK506, in the presence of their respective cytoplasmic immunophilin proteins, cyclophilin and FK506-binding protein. Many studies have used these immunosuppressant drugs and/or modern genetic techniques to disrupt calcineurin in model organisms such as yeast, filamentous fungi, plants, vertebrates, and mammals to explore its biological function. Recent advances regarding calcineurin structure include the determination of its three-dimensional structure. In addition, biochemical and spectroscopic studies are beginning to unravel aspects of the mechanism of phosphate ester hydrolysis including the importance of the dinuclear metal ion cofactor and metal ion redox chemistry, studies which may lead to new calcineurin inhibitors. This review provides a comprehensive examination of the biological roles of calcineurin and reviews aspects related to its structure and catalytic mechanism.

The effects of topical transforming growth factor-beta2 and anti-transforming growth factor-beta2,3 on scarring in pigs.

BACKGROUND: Transforming growth factor-b2 (TGF-b2) has been implicated in the inflammatory response and subsequent scarring during wound healing. OBJECTIVE: The experiment was designed to study the effects of a topical application of TGF-b2 and mouse monoclonal anti-TGF-b2,3 neutralizing antibody (anti TGF-b2,3) on the development of fibrosis during healing. METHODS: Sixteen full-thickness excision wounds were made in the paravertebral and thoracic area of four domestic pigs. On day 0, three wounds each were treated with: a) 5 mg of TGF-b2, b) 5 mg of 2% methylcellulose (mc), or c) 1.2 mg of anti-TGF-b2,3. As a vehicle for treatment of each wound methylcellulose 2% was used. Four wounds served as the untreated air-exposed control. Wounds were biopsied and the tissue sectioned and stained with hematoxylin and eosin on days 7, 14, and 45. Three blinded observers evaluated the wound specimens. RESULTS: Using computer-aided point count stereology on days 7, 14, and 45, we found a statistically significant increase (p <.05) in the number of nucleated cells in the TGF-b2-treated wounds as compared to the other control wounds. Wounds treated with anti-TGF-b2,3 had significantly (p <.05) fewer nucleated cells on days 7,14, and 45. Microscopically, the TGF-b2-treated wounds had a larger scar area as compared to anti-TGF-b2,3 and controls. CONCLUSION: Treating wounds with an antibody directed against TGF-b2 might be a useful clinical approach to reduce fibrosis.

Collagen fiber orientation as quantified by small angle light scattering in wounds treated with transforming growth factor-beta2 and its neutalizing antibody.

The purpose of this study was determine quantitative differences in collagen fiber orientation in a wound healing model in the presence of transforming growth factor-beta2 and anti-transforming growth factor-beta2,3 antibody. Full-thickness wounds were made in the paravertebral area of two young pigs. Wounds were treated once, topically, with either transforming growth factor-beta2 or anti-transforming growth factor-beta2 antibody, or with methylcellulose gel. Control wounds were left untreated. Tissue biopsies were obtained from each wound on days 7, 14 and 46 post wounding. Tissue sections were stained with hematoxylin and eosin, and collagen fiber preferred orientation was quantified using small angle light scattering. Our results indicated that wounds treated with transforming growth factor-beta2 and anti-transforming growth factor-beta2,3 antibody had a significantly higher degree of orientation of collagen fibers than normal unwounded skin on days 7, 14 and 46 (p < 0.001). Transforming growth factor-beta2- treated wounds had a higher degree of orientation of collagen fibers than control wounds on days 7 and 14 (p < 0.001), and control wounds displayed a higher degree of orientation than wounds treated with anti-transforming growth factor-beta2,3 and normal unwounded skin at all time points (p < 0.001). These results suggest that differences in the dermal collagen degree of orientation correlate with scarring, and show that small angle light scattering can be used quantitatively to assess differences in the collagen fiber architecture of dermal wounds.

Interaction of bacteriophage lambda protein phosphatase with Mn(II): evidence for the formation of a [Mn(II)]2 cluster.

The interaction of bacteriophage lambda protein phosphatase with Mn2+ was studied using biochemical techniques and electron paramagnetic resonance spectrometry. Reconstitution of bacteriophage lambda protein phosphatase in the presence of excess MnCl2 followed by rapid desalting over a gel filtration column resulted in the retention of approximately 1 equiv of Mn2+ ion bound to the protein. This was determined by metal analyses and low-temperature EPR spectrometry, the latter of which provided evidence of a mononuclear high-spin Mn2+ ion in a ligand environment of oxygen and nitrogen atoms. The Mn2+-reconstituted enzyme exhibited negligible phosphatase activity in the absence of added MnCl2. The EPR spectrum of the mononuclear species disappeared upon the addition of a second equivalent of Mn2+ and was replaced by a spectrum attributed to an exchange-coupled (Mn2+)2 cluster. EPR spectra of the dinuclear (Mn2+)2 cluster were characterized by the presence of multiline features with a hyperfine splitting of 39 G. Temperature-dependent studies indicated that these features arose from an excited state. Titrations of the apoprotein with MnCl2 provided evidence of one Mn2+ binding site with a micromolar affinity and at least one additional Mn2+ site with a 100-fold lower affinity. The dependence of the phosphatase activity on Mn2+ concentration indicates that full enzyme activity probably requires occupation of both Mn2+ sites. These results are discussed in the context of divalent metal ion activation of this enzyme and possible roles for Mn2+ activation of other serine/threonine protein phosphatases.

The evaluation of a cadexomer iodine wound dressing on methicillin resistant Staphylococcus aureus (MRSA) in acute wounds.

BACKGROUND: Many bacteria have become resistant to commonly-used antibiotics. OBJECTIVE: The purpose of this study was to examine the effect of a cadexomer iodine wound dressing on methicillin resistant Staphylococcus aureus (MRSA). METHOD: Partial thickness wounds were made on the backs of three pigs and inoculated with a known amount of MRSA. Wounds were treated with either cadexomer iodine dressing or vehicle dressing (without iodine), or they were left untreated. Three wounds from each treatment group per animal were cultured using quantitative scrub techniques after 24, 48, or 72 hours of treatment. CONCLUSIONS: The cadexomer iodine dressing significantly reduced MRSA and total bacteria in the wounds as compared to both the no treatment control and vehicle. No significant differences were observed in the number of bacteria recovered between the no treatment control and cadexomer (vehicle) treated wounds. Cadexomer iodine may be an effective agent for preventing proliferation of MRSA in wounds.

Effect of occlusion on cell proliferation during epidermal healing.

BACKGROUND: Occlusive dressings influence epithelization of superficial wounds by some unknown mechanism(s). OBJECTIVE: The effects of occlusion on epidermal cell proliferation in two types of wounds were examined. METHODS: Partial-thickness wounds and tape-stripped skin wounds were compared. An immunohistochemical technique, employing PC10 - a monoclonal antibody against proliferating cell nuclear antigen (PCNA) - was applied to formalin-fixed, paraffin-embedded porcine tissue sections. RESULTS: The number of PC10-positive cells was low during the migratory phase, then increased to a peak of proliferation 2 to 3 days after resurfacing. An overall increased proliferative response (mean = 21%) was seen in occluded compared to control partial-thickness wounds (day 10 postoperatively); an opposite effect of occlusion on epidermal proliferation was seen in tape-stripped skin. Occlusion decreased the proliferative response (mean = 42%) compared to air-exposure. CONCLUSION: Occlusion increased epidermal cell proliferation in wounds (where the entire surface epithelium and papillary dermis was removed), whereas an opposite effect was seen in tape-stripped skin from which only the stratum corneum had been removed.

Kinetic and spectroscopic analyses of mutants of a conserved histidine in the metallophosphatases calcineurin and lambda protein phosphatase.

Calcineurin belongs to a family of serine/threonine protein phosphatases that contain active site dinuclear metal cofactors. Bacteriophage lambda protein phosphatase is also considered to be a member of this family based on sequence comparisons (Lohse, D. L., Denu, J. M., and Dixon, J. E. (1995) Structure 3, 987-990). Using EPR spectroscopy, we demonstrate that lambda protein phosphatase accommodates a dinuclear metal center. Calcineurin and lambda protein phosphatase likewise contain a conserved histidine that is not a metal ligand but is within 5 A of either metal in calcineurin. In this study the conserved histidine in calcineurin was mutated to glutamine and the mutant protein analyzed by EPR spectroscopy and kinetic methods. Parallel studies with an analogous lambda protein phosphatase mutant were also carried out. Kinetic studies using paranitrophenyl phosphate as substrate showed a decrease in kcat of 460- and 590-fold for the calcineurin and lambda protein phosphatase mutants, respectively, compared with the wild type enzymes. With a phosphopeptide substrate, mutagenesis of the conserved histidine resulted in a decrease in kcat of 1,300-fold for calcineurin. With the analogous lambda protein phosphatase mutant, kcat decreased 530-fold compared with wild type lambda protein phosphatase using phenyl phosphate as a substrate. EPR studies of the iron-reconstituted enzymes indicated that although both mutant enzymes can accommodate a dinuclear metal center, spectroscopic differences compared with wild type proteins suggest a perturbation of the ligand environment, possibly by disruption of a hydrogen bond between the histidine and a metal-coordinated solvent molecule.

A comparative study of three occlusive dressings in the treatment of full-thickness wounds in pigs.

BACKGROUND: Little objective information is available on the influence of occlusive dressings on the healing of cutaneous full-thickness wounds. OBJECTIVE: Our purpose was to examine the effects of three occlusive dressings-two hydrocolloid dressings (Comfeel Ulcer Dressing, Coloplast A/S, Espergaerder, Denmark [hydrocolloid dressing A] and DuoDERM; ConvaTec, Princeton, N.J. [hydrocolloid dressing B]) and one polyurethane film dressing (OpSite, Smith & Nephew, Hull, U.K. [film dressing])-on tissue reactions, degree of inflammation, wound contraction, and epithelialization in full-thickness wounds in domestic pigs. METHODS: Standardized 20 mm full-thickness punch biopsy wounds were treated for 10 days. Healing was assessed by light microscopy and by planimetry. RESULTS: Material from both hydrocolloid dressings was phagocytosed as indicated by the presence of foam cells in the granulation tissue. Granulomatous tissue reactions around extracellular vacuoles were found in 10 of 12 hydrocolloid dressing B-treated wounds compared with one in hydrocolloid dressing A-treated wounds and in none of the 10 film dressing-treated wounds (p < 0.0001). Inflammation was significantly (p < 0.002) more pronounced in hydrocolloid dressing B-treated wounds. The extracellular vacuoles in the hydrocolloid dressing B group contained dressing material as demonstrated by Fourier transform infrared microscopy. There was a tendency (p < 0.07) towards a delayed entry into the contraction phase with hydrocolloid dressing B, but there was no significant difference in epithelialization between the three dressings. CONCLUSION: Wound tissue reactions to different hydrocolloid dressings vary depending on composition. The tissue reactions had no significant effect on wound contraction or epithelialization.

Suppression of prostaglandin H synthase-2 induction in human monocytes by in vitro or in vivo administration of interleukin 4.

IL-4 is a potent modulator of monocyte function. Our previous studies demonstrated that the suppression of monocyte matrix metalloproteinase production by IL-4 is a result of its inhibition of PGE2 synthesis, which was attributed to an effect on prostaglandin synthase. Here we report on the in vitro and in vivo effects of IL-4 on monocyte prostaglandin H synthase-2 (PGHS-2) and its regulation by second messengers. Stimulation of monocytes with either LPS or Con A resulted in the induction of PGHS-2 which was significantly inhibited by IL-4. Inhibition of PGHS-2 mRNA and protein was detected at 0.05 to 0.1 ng/ml of IL-4 with substantial suppression at 10 to 20 ng/ml. If added later than 2 hr after LPS, IL-4 failed to suppress PGHS-2, indicating that IL-4 acted early in the signaling cascade. Moreover, the ability of exogenously added PGE2 or Bt2cAMP to restore PGHS-2 production in IL-4-treated monocytes further suggested early disruption of the pathway. The early event inhibited by IL-4 did not involve suppression of phospholipase activity, because LPS-induced arachidonic acid release was relatively unaffected by IL-4. Unlike PGHS-2, PGHS-1, the constitutively expressed PGHS, was not modulated by IL-4. Thus, IL-4 appears to selectively block PGHS-2 synthesis, thereby blocking subsequent steps in the pathway leading to the production of matrix metalloproteinases. In an extension of these findings, we examined peripheral blood monocytes from cancer patients undergoing IL-4 therapy. In these cells the induction of PGHS-2 expression by LPS was significantly reduced compared to that of monocytes obtained prior to IL-4 therapy. Although perhaps not relevant as an antitumor mechanism, these findings have important implications in defining the potent anti-inflammatory activities of IL-4 in vitro and in vivo.

Early debridement of second-degree burn wounds enhances the rate of epithelization--an animal model to evaluate burn wound therapies.

The purpose of this study was to examine the rate of epithelization of second-degree burn wounds with use of two debridement times (early versus late). Burn wounds were randomly assigned to one of the following treatment groups: (1) control, no debridement, (2) early debridement at 24 hours after burning, or (3) late debridement at 96 hours after burning. Wounds from each treatment group were harvested, incubated to allow separation of the dermis and epidermis, and then examined macroscopically for complete epithelization. On day 7 after burning, the percentage of burn wounds completely epithelized was as follows: nondebrided, 41%, 24-hour early debridement, 75%, and 96-hour late debridement, 22%. Burn wounds that were excised 24 hours after burning enhanced the rate of healing as compared to 96 hour and nondebrided burn wounds.

Effects of an arginine-glycine-aspartic acid peptide-containing artificial matrix on epithelial migration in vitro and experimental second-degree burn wound healing in vivo.

Cells central to dermal tissue repair such as dermal fibroblasts and keratinocytes interact with arginine-glycine-aspartic acid (RGD)-containing proteins of the extracellular matrix such as fibronectin. It has been shown that synthetic peptides containing this RGD sequence can also support cell attachment and migration in vitro. We therefore set out to test whether the use of these peptides, when formulated as a synthetic RGD-peptide matrix consisting of peptide complexed with hyaluronic acid, would have an effect on the rate of epithelial migration and healing of experimental wounds. Evaluation consisted of measuring he extent of epithelial outgrowth from human dermal explants and the epithelization of experimental second-degree burn wounds in pigs. We show here that the RGD-peptide matrix supports epithelial sheet migration from explants in a dose-dependent manner. In second-degree burn wounds in pigs, wounds treated with daily applications of the RGD-peptide matrix under occlusion resurfaced at a significantly faster rate (day 7 = 57% completely epithelized) than wounds treated with hyaluronic acid under occlusion (day 7 = 13% completely epithelized, p < 0.01), occlusion alone (day 7 = 13% completely epithelized, p < 0.01), or air exposed (day 7 = 0% completely epithelized, p < 0.001). Histologic examination showed that wounds treated with the RGD-peptide matrix also had thicker epithelial covering and greater granulation tissue deposition than occluded, air-exposed, and hyaluronate-treated wounds. These data therefore show that the use of RGD-peptide matrix induces faster explant epithelial migration and results in faster healing of experimental second-degree burns.

In vivo 3-D distributions of electric fields in pig skin with rectangular pulse electrical current stimulation (RPECS).

We developed stimulating and detecting electrodes. We experimentally examined three dimensional (3-D) distributions of electric fields in living pig skin under and around the stimulating electrodes with the detecting electrodes and rectangular pulsed electrical current stimulation (RPECS). We verified our previous physical assumption, E approximately I/(A sigma dz), in the skin under the electrode, where E, I, A and sigma dz respectively represent the electric field, the externally imposed peak current, the cross sectional area of the stimulating electrode and the perpendicular conductivity of the skin. Pulses were 30 mA, 140 microseconds and 128 pulses per second (pps). These parameters were previously used in our laboratory to enhance cutaneous regeneration, in vivo, with RPECS.

Conductivities of pig dermis and subcutaneous fat measured with rectangular pulse electrical current.

We examined experimentally the relationship between perpendicular and tangential electrical conductivities, sigma, and peak current density J, in pig skin dermis and subcutaneous fat specimens by using a four-electrode measuring system with rectangular pulse electrical current (RPEC). We also investigated the relationship of the conductivity, sigma, vs. pulse rate, f. The rates were selected at 8, 32, 64, and 128 pulses per second (pps), and the pulse width was fixed at 140 microseconds. These values are often used in vivo to enhance cutaneous regeneration with RPEC stimulation. It was found that the conductivities may be approximated to be [equation: see text] for the skin dermis and [equation: see text] for the subcutaneous fat in the conditions of this experiment. These findings implies that the conductivities of pig skin dermis and subcutaneous fat are anisotropic, i.e., sigma x = sigma y not equal to sigma z. It was also found that the conductivities are independent of current density and pulse rate in the current range from 20 microA/cm2 to 120 mA/cm2.

Calcineurin subunit interactions: mapping the calcineurin B binding domain on calcineurin A.

Recombinant forms of the A and B subunits of the protein phosphatase calcineurin were produced in Escherichia coli, reconstituted into a heterodimer and purified to homogeneity. The reconstituted heterodimer exhibited properties like that of bovine brain calcineurin. This included calmodulin-stimulated activity and a subunit stoichiometry and Stokes radius consistent with native-like structure. In order to map the region on the A subunit where calcineurin B binds, a series of overlapping 20-residue peptides corresponding to this putative domain were synthesized. Using isolated calcineurin A and B subunits, an assay that relied upon peptide inhibition of calcineurin B stimulation of calcineurin A activity was developed. All five peptides, but not a control peptide, inhibited calcineurin B-dependent stimulation of calcineurin A although with different potencies. The three most effective inhibitory peptides spanned calcineurin A residues 338-377. These three peptides also altered the electrophoretic mobility of the isolated calcineurin B subunit during native polyacrylamide gel electrophoresis indicating a direct interaction between these peptides and calcineurin B. The peptide corresponding to residues 348-367 was also able to block binding of calcineurin B to the catalytic subunit.

Collagenase during burn wound healing: influence of a hydrogel dressing and pulsed electrical stimulation.

Epithelialization of second-degree burn wounds is known to be accelerated by topical treatment with hydrogel dressings and further enhanced by pulsed electrical stimulation compared with no treatment (air exposure). Tissue collagenase has been proposed to be involved during the process of epithelialization. In the present study collagenase levels were examined in partial-thickness burn wounds in the skin of four domestic pigs. Collagenase levels, assayed on postburn days 1 to 10, were substantially reduced in deblistered and air-exposed burn wounds compared with excisional partial-thickness wounds. Early application of hydrogel dressing to the burn wounds was accompanied by elevated collagenase activities and an increased inflammatory reaction in dermis. Addition of pulsed electrical stimulation increased (p < 0.001) collagenase levels twofold above those with hydrogel alone during initiation of epithelialization (postburn days 3 and 4). These results suggest that collagenase is closely linked to wound epithelialization.

Are excessive granulation tissue formation and retarded wound contraction due to decreased collagenase activity in wounds in tight-skin mice?

Wound contraction is delayed in tight-skin mice but the mechanism(s) are unknown. The purpose of this study was to investigate collagenase levels and the formation of granulation tissue in experimental wounds in tight-skin mice. One full-thickness skin excision (20 x 20 mm) was made on the back of nine tight-skin and eight normal mice. Granulation tissue analyses were performed 7 days post-operatively. The collagenase activity was determined by the use of a radiolabelled telopeptide-free collagen substrate, and the amount of granulation tissue was determined gravimetrically. Wound contraction was delayed (P < 0.001) in tight-skin mice (mean 22%) compared with normal mice (mean 46%). The collagenase activity was decreased (P < 0.05) by 40%, whereas the quantity of granulation tissue was increased (P < 0.001) by 60% in the wounds of tight-skin mice. Decreased collagenase content may provide one explanation for the delayed contraction of full-thickness wounds in tight-skin mice. Furthermore, this animal would model may prove useful in the understanding of the pathogenesis, and in exploration of treatment, of excessive granulation tissue formation during wound healing.