The State of Burn Care Training During Plastic Surgery Residency.

INTRODUCTION: There is an ongoing shortage of burn specialists, and workforce reports suggest possible hurdles attracting plastic surgeons into burn care. The purpose of this study was to (1) determine the state of burn care in plastic surgery residency and (2) identify what barriers might exist for plastic surgeons pursuing a practice that involves burn care. METHODS: Surveys were distributed to North American plastic surgery program directors and residents, respectively, during the 2018-2019 academic year. RESULTS: Fifty-eight program directors (response, 54%) and 320 plastic surgery residents (response, 30%) participated. Burn care was felt to be an important component in training by most program directors (USA, 88%; Canada, 100%) and residents (USA, 87%; Canada, 99%). The majority of program directors included a burn unit rotation (USA, 88%; Canada, 90%). Rotations for integrated residents averaged 2.5 months and most commonly occurred during second year; independent residents spent 1.2 months on rotation, usually in first year. Three-quarters of American residents were interested in a career that involves burn care in some capacity, primarily burn reconstruction (40%). Factors that would discourage a trainee from practicing burn care in the future included the nature of burn care (60%) and burn operations (45%), the on-call commitment (39%), and a narrow scope of practice (38%). DISCUSSION: This study challenges the belief that plastic surgery trainees are disinterested in burn care. Burn surgery remains an important component of training programs, and we propose several steps to encourage greater interest and participation in the burn surgery workforce.

Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2.

Epithelial-mesenchymal transition (EMT), characterized by loss of epithelial adhesion and gain of mesenchymal features, is an important mechanism to empower epithelial cells into the motility that occurs during embryonic development and recurs in cancer and fibrosis. Whether and how EMT occurs in wound healing and fibrosis in human skin remains unknown. In this study we found that migrating epithelial cells in wound margins and deep epithelial ridges had gained mesenchymal features such as vimentin and FSP1 expression. In hypertrophic scars, EMT-related genes were elevated along with inflammatory cytokines, indicating a causal relationship. To reconstitute EMT in vitro, normal human skin and primary keratinocytes were exposed to cytokines such as tumor necrosis factor-alpha (TNF-alpha), resulting in expression of vimentin, FSP1, and matrix metalloproteinases. Moreover, TNF-alpha-induced EMT was impaired by antagonists against bone morphogen proteins (BMP) 2/4, suggesting that BMP mediates the TNF-alpha-induced EMT in human skin. Indeed, TNF-alpha could induce BMP-2 and its receptor (BMPR1A) in human skin and primary keratinocytes, and BMP2 could induce EMT features in skin explants and primary keratinocytes. In summary, we uncovered EMT features in both acute and fibrotic cutaneous wound healing of human skin. Moreover, we propose that the mesenchymal induction in wound healing is motivated by TNF-alpha, in part, through induction of BMP.

Venous Thromboembolism Chemoprophylaxis in Burn Patients: A Literature Review and Single-Institution Experience.

Hospitalized burn patients meet the criteria for Virchow's triad (endothelial damage, hypercoagulability, and stasis), predisposing them to venous thromboembolism (VTE). Although the disease burden of VTE suggests a need for prevention in this population, unreliable reported VTE rates, costly and complicated prophylaxis regimens, and chemoprophylaxis risks have prevented the establishment of a universal protocol. This paper reviews thromboprophylaxis practices both in the literature and at our own institution. A systematic review was conducted according to PRISMA guidelines identifying studies pertaining to VTE chemoprophylaxis in burn patients. Additionally, medical records of patients admitted to an American Burn Association-verified burn center between June 2015 and June 2019 were retrospectively reviewed for demographics, chemoprophylaxis, and presence of VTE defined as either deep vein thrombosis (DVT) or pulmonary embolism (PE). Thirty-eight studies met inclusion criteria. In the 12 studies that reported VTE incidence, rates ranged widely from 0.25% to 47.1%. The two largest retrospective studies (n = 33,637 and 36,638) reported a VTE incidence of 0.61% and 0.8% in populations with unknown or inconsistently recorded chemoprophylaxis. Throughout the literature, prevention protocols were mixed, though a trend toward using dose-adjusted subcutaneous low molecular weight heparin based on serum anti-factor Xa level was noted. At our burn center, 1,068 patients met study criteria. At-risk patients received a simple chemoprophylaxis regimen of 5000U of subcutaneous unfractionated heparin every 8 hours. No routine monitoring tests were performed to limit cost. Nine cases of DVT and two cases of PE were identified with an incidence of 0.84% and 0.19%, respectively, and a total VTE incidence of 1.03%. Only one patient developed heparin-induced thrombocytopenia (HIT). No cases of other heparin-associated complications were observed. VTE incidence rates reported in the literature are wide-ranging and poorly capture the effect of any one chemoprophylaxis regimen in the burn population. Our center uses a single, safe, and cost-effective protocol effecting a low VTE rate comparable to that of large national retrospective studies.

The Impact of No Next of Kin Decision Makers on End-of-Life Care.

For critically ill burn patients without a next of kin, the medical team is tasked with becoming the surrogate decision maker. This poses ethical and legal challenges for burn providers. Despite this frequent problem, there has been no investigation of how the presence of a next of kin affects treatment in burn patients. To evaluate this relationship, a retrospective chart review was performed on a cohort of patients who died during the acute phase of their burn care. Variables collected included age, gender, length of stay, total body surface area, course of treatment, and presence of a next of kin. In total, 67 patients met the inclusion criteria. Of these patients, 14 (21%) did not have a next of kin involved in medical decisions. Patients without a next of kin were significantly younger (P = .02), more likely to be homeless (P < .01), had higher total body surface area burns (P = .008), had shorter length of stay (P < .001), and were five times less likely to receive comfort care (P = .01). Differences in gender and ethnicity were not statistically significant. We report that patients without a next of kin present to participate in medical decisions are transitioned to comfort care less often despite having a higher burden of injury. This disparity in standard of care demonstrates a need for a cultural shift in burn care to prevent the suffering of these marginalized patients. Burn providers should be empowered to reduce suffering when no decision maker is present.

The Impact of Peer Support Group Programs on Psychosocial Outcomes for Burn Survivors and Caregivers: A Review of the Literature.

Peer support group programs are often recommended for burn survivors as a way to facilitate their psychosocial recovery and reintegration into the community. Such programs provide opportunities for burn patients and their caretakers to access emotional and informational support from healthcare providers and other survivors in inpatient or outpatient settings. Despite their popularity, however, there is little information currently available on the efficacy of these groups. In response, we reviewed the existing literature on peer support group programs and their impacts on psychosocial outcomes for burn survivors and their caregivers. A systematic review of the literature utilizing PubMed, PsycINFO, and Medline databases was conducted for articles published between 1990 and 2018. Twenty-five articles including inpatient, outpatient, integrative peer support groups, and burn camps met our inclusion criteria. All inpatient peer support group program articles (n = 4) reported associations with psychosocial improvements. Integrative peer support group program articles (n = 2) reported associations with social integration and reduction in post-traumatic stress and anxiety. All outpatient peer support group program articles (n = 8) demonstrated associations with psychosocial outcomes involving life satisfaction, acceptance of self, and reduced levels of isolation. Findings were less consistent for burn camps: eight articles suggested improvements in psychological outcomes while three articles reported no significant psychosocial effects. Although these results are encouraging, further study is indicated both to replicate these findings, and to determine the optimal implementation of inpatient and outpatient peer support programs.

Hypoglycemic episodes predict length of stay in patients with acute burns.

Hypoglycemic episodes are associated with worse hospital outcomes. All adult patients admitted to our burn center from 2015 to 2019 were retrospectively reviewed. Patient demographics and burn characteristics were recorded. The primary outcome was mortality, and secondary outcomes were total length-of-stay and intensive care unit length-of-stay. All patients experiencing at least one hypoglycemic episode were compared to patients who did not experience hypoglycemia. There were 914 patients with acute burns admitted during the study period, 33 of which (4%) experienced hypoglycemic episodes. Of these, 17 patients (52%) experienced a single hypoglycemic episode, while the remainder experienced multiple hypoglycemic episodes. Patients with one or more hypoglycemic events were matched to non-hypoglycemic controls using propensity matching. Patients that experienced hypoglycemia had significantly less TBSA involvement (5% vs. 13%,median, p < 0.0002), higher prevalence of diabetes (48% vs. 18%, p < 0.0001), higher mortality (18% vs. 7%, p = 0.01), longer total length-of-stay (22 vs. 8 days, median, p < 0.0001), and longer ICU length-of-stay (12 vs. 0 days, median, p < 0.0001). A single hypoglycemic episode was associated with prolonged total (IRR = 1.91, p < 0.0001) and ICU length-of-stay (IRR = 3.86, p < 0.0001). Hypoglycemia was not associated with higher mortality in the survival analysis (p = 0.46).

Intermediate Skin Substitutes Are Unnecessary in Small (<10% TBSA) Burns.

The use of intermediate skin substitutes between debridement and final autografting is routine for many practitioners. Materials such as xenografts and allografts have been promoted to help with wound coverage before autografting. However, there is limited data for their use in relatively small burn wounds (<10% TBSA). In this study, we analyzed the outcomes of 100 consecutive patients who underwent autografting for burns <10% TBSA at our American Burn Association-verified burn unit in the absence of intermediate skin substitute use. We retrospectively analyzed 100 patients who underwent split thickness skin graft autografting for burns <10% TBSA between November 2017 and June 2019. No patients were treated with intermediate skin substitutes. Analysis included basic demographics, comorbidities, TBSA burned, mechanism of burn, time to grafting, if grafting was performed in a single procedure or staged, graft loss (>50% graft failure), and time to complete healing (no further wound care required). Twelve patients (12%) had unpredictable graft beds, and their procedure was staged. These patients underwent surgical debridement and were dressed in antimicrobial dressing for an average of 5 days before autografting. No patients had intermediate skin substitutes between procedures. Eighty-eight patients (88%) were debrided and grafted in a single stage. In the staged group, there was a 0% rate of graft failure compared with 9.1% rate of graft failure in the primarily grafted group (P = .004). There was a similar length of stay and time to complete healing in the staged group and primarily grafted group (P = .496 and P = .571). There was a significantly shorter time from injury to first procedure between the staged group and the primarily grafted group (8.7 days and 13.5 days, P = .014). In the eight instances of graft failure, infection or inadequate debridement was the cause. Seven of these eight cases required further surgical intervention. Intermediate skin substitutes are an unnecessary step in grafting small burns. These add only complexity and cost to patient care. Many patients can be debrided and grafted in a single stage. Debridement alone with delayed grafting is a highly effective surgical method when the wound bed is not suitable for immediate grafting. The use of intermediate skin substitutes in small burns requires further investigation as this study finds low benefit for this product.

The Homelessness Crisis and Burn Injuries: A Cohort Study.

The United States is facing a growing homelessness crisis. We characterize the demographics and outcomes of homeless patients who sustain burn injury and compare them to a cohort of domiciled patients. A retrospective cohort study was performed at the Los Angeles County + University of Southern California Regional Burn Center for consecutive acute burn admissions in adults from June 1, 2015, to December 31, 2018. Patients were categorized as either domiciled or homeless at the time of their injury. Prevalence rates were estimated using data from the regional homeless count. From 881 admissions, 751 (85%) had stable housing and 130 (15%) were homeless. The rate of burn injury requiring hospitalization for homeless adults was estimated at 88 per 100,000 persons. Homeless patients had a significantly larger median burn size (7 vs 5%, P < .05) and a greater rate of flame burns (68 vs 42%, P < .001). For the homeless, rates of assault and self-inflicted injury were 4- (18 vs 4%, P < .001) and 2-fold higher (9 vs 4%, P < .001), respectively. Homeless patients had higher rates of mental illness (32 vs 12%, P < .001) and substance abuse (88 vs 22%, P < .001), and were less likely to follow-up as outpatients (54 vs 87%, P < .001). There was no difference in mortality. Homeless patients had a longer median length of stay (LOS; 11 vs 7 days, P < .001) without significant differences in LOS per percentage TBSA. Homeless individuals should be considered a high-risk population for burn injury. This distinction serves as a call to action for the development of burn prevention strategies.

Small Pediatric Burns Can Be Safely Managed on an Outpatient Basis.

American Burn Association (ABA) guidelines recommend that all pediatric burns be transferred to a burn center if their presenting hospital lacks the necessary personnel or equipment for their care. Our institution often treats small burns (<10% TBSA) in pediatric patients in an ambulatory setting with a nondaily dressing. The aim of this study was to determine whether small pediatric burns could be safely managed on an outpatient basis. A retrospective review at a single ABA-verified burn center was conducted, including 742 pediatric patients presenting to the burn evaluation clinic in a 3-year period. Postburn day, age, sex, TBSA, burn etiology, body area burned, burn dressing type, outpatient versus inpatient management, reason(s) for admission, and any operative intervention were collected. Overall, the most common burn etiologies were scald (68%), contact (20%), and flame (5%). In this cohort, 14% (101) of patients were admitted on evaluation to the burn center with a mean TBSA of 9%. The remaining 86% (641) of patients were treated outpatient with a mean TBSA of 3%. Of those who were treated outpatient, 96% (613) successfully completed outpatient care and 4% (28) were subsequently admitted. The patients who were successfully managed in an ambulatory setting had a mean TBSA of 3%, whereas the patients who failed outpatient care had a mean TBSA of 4%. The primary reason for the subsequent admission of these patients was nutrition optimization (61%). The vast majority of small pediatric burns can be effectively treated on an outpatient basis with a nondaily dressing.

Stimulant Abuse in Burn Patients Is Associated With an Increased Use of Hospital Resources.

Stimulant (cocaine, methamphetamine, and amphetamine) abuse compromises the peripheral vasculature through endothelial injury. In combination with the physiologic derangements seen in burn injuries, patients abusing stimulants may have additional impairments in wound healing. A retrospective review from July 1, 2015 to July 1, 2018 was performed at an American Burn Association-verified burn center. Patients with positive urine toxicology results for stimulants (ST(+)), and those without (ST(-)), who sustained burn injuries were identified and matched by age and TBSA. The primary outcome was mortality, and secondary outcomes included total length of stay (LOS), and need-for-surgery (grafting). In total, 130 patients ST(+) and 133 ST(-) patients were identified. There were no significant differences in age (40.9 ± 13.5 vs 39.2 ± 23.7 years, P = 0.46), Inhalation Injury (12.3 vs 9.0%, P = 0.39), or nutritional status (prealbumin: 17.3 ± 6.1 vs 17.1 ± 12.7 mg/dl, P = 0.66; albumin: 3.5 ± 0.6 vs 3.6 ± 0.7 g/dl, P = 0.45). There were no differences in mortality (6.1 vs 4.5%, P = 0.55), intensive care unit LOS (9.3 ± 16.5 vs 10.2 ± 20.9 days, P = 0.81), wound infections (15.4 vs 23.9%, P = 0.07), or wound conversion (6.9 vs 3.0%, P = 0.14). ST(+) patients had a significantly longer LOS (15.0 ± 16.9 vs 10.7 ± 17.3 days, P = 0.04), greater tobacco use (56.9 vs 18.0%, P = 0.00001), and greater need for grafting (54.6 vs 33.1%, P = 0.0004). ST(+) patients require more hospital resources-surgical operations and hospital days-than ST(-) patients. The increased need for surgical intervention may partially explain the increase in hospital days, in addition to the observation that ST(+) patients had more complex disposition issues than ST(-) patients.

Tumor necrosis factor-alpha induced expression of matrix metalloproteinase-9 through p21-activated kinase-1.

BACKGROUND: Expressed in embryonic development, matrix metalloprotein-9 (MMP-9) is absent in most of developed adult tissues, but recurs in inflammation during tissue injury, wound healing, tumor formation and metastasis. Expression of MMP-9 is tightly controlled by extracellular cues including pro-inflammatory cytokines and extracellular matrix (ECM). While the pathologic functions of MMP-9 are evident, the intracellular signaling pathways to control its expression are not fully understood. In this study we investigated mechanism of cytokine induced MMP-9 with particular emphasis on the role of p21-activated-kinase-1 (PAK1) and the down stream signaling. RESULTS: In response to TNF-alpha or IL-1alpha, PAK1 was promptly activated, as characterized by a sequential phosphorylation, initiated at threonine-212 followed by at threonine-423 in the activation loop of the kinase, in human skin keratinocytes, dermal fibroblasts, and rat hepatic stellate cells. Ectopic expression of PAK1 variants, but not p38 MAP kinase, impaired the TNF-alpha-induced MMP-9 expression, while other MMPs such as MMP-2, -3 and -14 were not affected. Activation of Jun N-terminal kinase (JNK) and NF-kappaB has been demonstrated to be essential for MMP-9 expression. Expression of inactive PAK1 variants impaired JNK but not NF-kappaB activation, which consequently suppressed the 5'-promoter activities of the MMP-9 gene. After the cytokine-induced phosphorylation, both ectopically expressed and endogenous PAK1 proteins were promptly accumulated even in the condition of suppressing protein synthesis, suggesting the PAK1 protein is stabilized upon TNF-alpha stimulation. Stabilization of PAK1 protein by TNF-alpha treatment is independent of the kinase catalytic activity and p21 GTPase binding capacities. In contrast to epithelial cells, mesenchymal cells require 3-dimensional type-I collagen in response to TNF-alpha to massively express MMP-9. The collagen effect is mediated, in part, by boost JNK activation in a way to cooperate the cytokine signaling. CONCLUSION: We identified a novel mechanism for MMP-9 expression in response to injury signals, which is mediated by PAK1 activation and stabilization leading JNK activation.

Alpha1-antichymotrypsin activity correlates with and may modulate matrix metalloproteinase-9 in human acute wounds.

Matrix metalloproteinase-9 (MMP-9) plays a central role in many physiologic processes including acute and the chronic wounds. MMP-9 is not routinely expressed in healthy tissues but is promptly expressed as a proenzyme and converted into active enzyme after tissue injury. The mechanisms involved, including the activators and inhibitors for this enzyme in human tissue remain largely obscure. We recently identified alpha1-antichymotrypsin (alpha1-ACT), an acute phase factor, as a potent inhibitor controlling activation of pro-MMP-9 by human skin. The aim of this study is to establish the clinical relevance of the inhibitor in cutaneous wound healing. Fluids from acute burn blisters and conditioned media from skin explants of burn patients were analyzed. We observed that the presence pro-MMP-9 and its activation correlated with the proximity to and degree of injury. Early after trauma, massive levels of wound alpha1-ACT were associated with an absence of pro-MMP-9 activation. Conversely, the active MMP-9 occurs simultaneously with inactivation of alpha1-ACT. Our results suggest a role for alpha1-ACT as a physiologic inhibitor of MMP-9 activation in human wound healing.

Burn surge for Los Angeles County, California.

OBJECTIVES: Los Angeles County, CA is a participant in the Hospital Preparedness Program. One expectation of the program is that the county be prepared to surge for trauma and burn based on the population size. Los Angeles County has approximately 10 million residents and this translates to a required surge capacity of 150 burn beds. MATERIALS: The Los Angeles County Emergency Medical Services Agency (LA EMSA) has taken the lead for this project. This article describes the steps taken to create a burn surge plan for the county. RESULTS: The burn surge plan includes a series of policies and procedures with topics such as: activation, field triage, Emergency Department Assessment/Treatment, and Burn Resource Hospital Treatment Guidelines. DISCUSSION: Education, equipment, and supply needs and transfer agreements are discussed. Costs associated with the project are outlined.

Combination therapy: Etanercept and intravenous immunoglobulin for the acute treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is an autoimmune condition with significant morbidity and mortality. METHODS: A retrospective review was performed at a single institution. All patients admitted to the LAC+USC burn unit from May 1st 2015-January 1st 2018 with a histologic diagnosis of SJS/TEN were reviewed. Patient characteristics and outcomes were recorded. These outcomes were compared to our previously published cohort. RESULTS: Thirteen total consecutive SJS/TEN patients were treated with etanercept. Compared to non-etanercept treated patients, etanercept-treated patients did not experience a significant difference in mortality (15.4% vs. 10%, P=0.58), ICU days (6.9 vs. 15.1, P=0.08), length-of-stay (9.8 vs 16.4, P=0.11), or infections (38.5% vs. 57.5%, P=0.58). The standardized mortality ratio in etanercept-treated patients was 0.44 (95% CI, 0.21, 0.65). In general, etanercept-treated patients had higher SCORTENs (3 vs. 2, P=0.03) and longer delays to presentation (5.2 vs. 2.7 days, P<0.01). CONCLUSIONS: Etanercept can be considered in the treatment of SJS/TEN patients in addition to IVIg, and supportive care in a burn unit.

Do Websites Provide What Applicants Need? Plastic Surgery Residency Program Websites Versus Applicant Self-reported Needs.

BACKGROUND: Plastic surgery residency program websites (PSRWs) remain a major resource for applicants to one of the most competitive specialties in medicine, yet it is unclear how the website content aligns with information applicants need. OBJECTIVE: To evaluate PSRWs and whether they are meeting applicant needs. METHODS: An anonymous online survey of 2016 plastic and reconstructive surgery applicants evaluated the use of PSRWs and information desired. Two researchers then independently analyzed all 93 PSRWs in the United States to determine whether the websites met the needs of applicants based on a quantitative scoring system. RESULTS: Out of 369 total applicants to plastic surgery, the survey was sent to the 189 applicants to University of Southern California, and 87 responded (46% response rate). Ninety-eight percentage of respondents used websites during the application process. For 31%, websites served as the only source of information. Websites were moderately (60%) and only slightly useful (32%). For 22% and 34%, the quality of a website influenced their decision to apply or interview, respectively. Out of the 22 common components between the applicant survey and scoring assessment of websites, there was a significant difference in 17 components (77%) between those rated as "important" by applicants and availability of the corresponding component on websites (P < 0.05). Average (SD) score among websites was 18.7 (5.3) out of 49 maximum points (36.9%). Over 30% of websites displayed broken links or missing or outdated information. Only 19.6% displayed a link to provide website feedback. CONCLUSIONS: PSRWs commonly include pertinent information that is useful; however, most are lacking components valued by applicants. These findings can help guide the design, content, and improvement of PSRWs to be quality resources for applicants.

Acute Fluid Management of Large Burns: Pathophysiology, Monitoring, and Resuscitation.

This article reviews the pathophysiology of large burn injury and the extreme fluid shifts that occur in the hours and days after this event. The authors focus on acute fluid management, monitoring of hemodynamic status, and end points of resuscitation. Understanding the need and causes for fluid resuscitation after burn injury helps the clinician develop an effective plan to balance the competing goals of normalized tissue perfusion and limited tissue edema. Thoughtful, individualized treatment is the best answer and the most effective compromise.

Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs.

Burn injuries are a leading cause of morbidity including prolonged hospitalization, disfigurement, and disability. Currently there is no Food and Drug Administration-approved burn therapeutics. A clinical distinction of burn injuries from other acute wounds is the event of the so-called secondary burn wound progression within the first week of the injury, in which a burn expands horizontally and vertically from its initial boundary to a larger area. Therefore, an effective therapeutics for burns should show dual abilities to prevent the burn wound progression and thereafter promote burn wound healing. Herein we report that topically applied F-5 fragment of heat shock protein-90α is a dual functional agent to promote burn wound healing in pigs. First, F-5 prevents burn wound progression by protecting the surrounding cells from undergoing heat-induced caspase 3 activation and apoptosis with increased Akt activation. Accordingly, F-5-treated burn and excision wounds show a marked decline in inflammation. Thereafter, F-5 accelerates burn wound healing by stimulating the keratinocyte migration-led reepithelialization, leading to wound closure. This study addresses a topical agent that is capable of preventing burn wound progression and accelerating burn wound healing.

Interleukin-1alpha-induced proteolytic activation of metalloproteinase-9 by human skin.

BACKGROUND: Increased activity of matrix metalloproteinase-9 (MMP-9) has been well documented in many diseases associated with inflammation, such as chronic wounds, bullous pemphigoid, liver failure, and tumor metastases. The mechanism for the proteolytic activation of pro-MMP-9 in human tissue still remains unknown. METHODS: We investigated this mechanism through reconstitution of an inflammatory condition in normal human skin, and epidermal and dermal cells derived from skin. Normal human skin was cultured with exogenous cytokines associated with inflammation and tissue repair. MMP-9 induction and activation were measured, and potential mechanisms were probed by inhibitors. RESULTS: Pathophysiologic concentrations of interleukin (IL)-1alpha rapidly induced pro-MMP-9 synthesis by human skin. In contrast, IL-1-induced activation of pro-MMP-9 was a slow process, which required 3 days. Tumor growth factor-beta induced pro-MMP-9 but failed to promote activation of the precursor. When the skin was stimulated with the combination of tumor growth factor-beta and IL-1alpha, substantial induction and activation of pro-MMP-9 occurred. This IL-1 induced activation of pro-MMP-9 was observed in intact skin but not in isolated dermal fibroblasts or keratinocytes. IL-1-induced activation of pro-MMP-9 was inhibited by chymostatin, a chymotrypsinlike proteinase inhibitor. Furthermore, IL-1alpha decreased tissue inhibitor of metalloproteinase 1 without changing MMP-9 activator activity. CONCLUSIONS: The proteolytic activation of pro-MMP-9 in skin inflammatory diseases likely occurs via a pathway including IL-1alpha. The activation is mediated by downregulation of tissue inhibitor of MMP-1 and involves an as yet unidentified chymotrypsinlike proteinase.

Wound-healing perspectives.

Wound-healing in the skin is a complex orchestration of cellular processes, which has been perfected throughout the eons of phylogeny. It has so many coordinated biologic processes invoked both simultaneously and in a regulated orderly fashion that it has been likened to a recapitulation of gestation. Part of the problem with studying wound healing is in analyzing the processes independently and then seeing how they fit together and influence each other. This article discusses selected and recent scientific observations that have given insight into the biology of human skin wound healing. The article then discusses selected clinical advances that are based less on evidence-based observation and more on what works in practice and promotes wound healing.