Hypertrophic scarring is a common dermal fibroproliferative disorder that leads to poor quality wound healing, prolongs rehabilitation, and increases morbidity following major thermal and other injuries to the deep dermis. Local and systemic transforming growth factor (TGF)-beta has been implicated as a fibrogenic cytokine in the pathogenesis of many fibrotic disorders, whereas interferon (IFN) alpha-2b may improve the pathologic features of dermal fibrosis directly or by antagonizing the effects of TGF-beta and histamine. Nine patients with severe hypertrophic scarring were evaluated for 8 weeks before treatment with subcutaneous recombinant IFN alpha-2b, 2 x 10(6) IU three times per week for 24 weeks. Clinical assessment was performed using standardized photography, a burn scar assessment tool, and serial scar volume measurements. Monthly measurements of serum TGF-beta and plasma Ntau-methylhistamine were made prior to, during, and after IFN alpha-2b therapy and compared with 27 age-matched controls. Serial biopsies of the hypertrophic scars and normal skin were performed for evaluation of mast cell numbers. Significant improvement in scar assessment occurred in 7 of 9 patients, and 3 of 9 demonstrated significant reductions in scar volume with interferon therapy beyond that occurring during the 8-week control period. For the entire group, mean rates of improvement were significantly better during interferon therapy with no recurrence following treatment. Before interferon therapy, serum TGF-beta was significantly higher in the burn patients with hypertrophic scarring than in a control population (123.04 +/- 36.48 vs. 56.85 +/- 8.38 ng/ml, p < 0.05). Within 3 months of IFN alpha-2b therapy, serum TGF-beta levels fell significantly and remained within the normal range during therapy and after interferon therapy was stopped. Plasma Ntau-methylhistamine levels were also significantly elevated in the hypertrophic scar patients as compared with age and sex-matched controls (153.6 +/- 92.07 vs. 48.3 +/- 28.9 pg/ml, p < 0.05), and significant reductions were achieved with interferon therapy and maintained after interferon was discontinued. Paired biopsies of hypertrophic scarring and normal tissue demonstrated increased numbers of mast cells in hypertrophic scars compared with normal uninjured skin from the same patients (2.65 +/- 1.63 vs. 1.04 +/- 0.62 cells/high power field, p < 0.001); however, no significant change in mast cell content of the hypertrophic scars accompanied interferon therapy. Patients with severe hypertrophic scarring demonstrate increased levels of serum TGF-beta and plasma Ntau-methylhistamine following thermal injury. A significant clinical improvement in scar quality and volume occurred during IFN alpha-2b therapy, which was associated with normalization of serum TGF-beta and plasma Ntau-methylhistamine levels. A double-blind, placebo-controlled trial will be required to further assess the usefulness of subcutaneous treatment with IFN alpha-2b for the treatment of hypertrophic scarring.
From 1977 to 1987, 1705 thermally injured patients were admitted to the Firefighters' Burn Center at the University of Alberta Hospitals. Thirteen hundred forty-four were male (78.8%) and 361 were female (21.2%), with a mean total burn surface area (TBSA) of 15.1 (SEM +/- 0.4%) and a range of 1% to 99% TBSA. Sixteen hundred thirty-five patients survived to be discharged from hospital, with an overall survival rate of 95.9%. One hundred twenty-four burn patients (7.3%) suffered concomitant inhalation injury diagnosed by bronchoscopy. Patients with inhalation injury suffered from larger TBSA (39.7% +/- 2.8% versus 12.2% +/- 0.3%; p less than 0.01) than those without inhalation injury. Inhalation injury increased the number of deaths from burn injury (34.7% versus 1.7%; p less than 0.01) independent of age and TBSA. Inhalation injury was associated with a threefold prolongation of hospital stay (23.7 +/- 0.7 versus 74.4 +/- 6.2 days; p less than 0.01) and was independent of age and TBSA. Multifactorial probit analysis was performed for both inhalation- and noninhalation-injured burned patients to allow TBSA and age adjusted rates of mortality for the burn population presented. The maximum detrimental effects of inhalation injury in burn patient outcome occurred when it coexisted with moderate (15% to 29% TBSA) to large (30% to 69% TBSA) thermal injuries. These data demonstrate that inhalation injury is an important comorbid factor in burn injury that increases the number of deaths substantially. Most importantly such injuries also independently prolong the duration of hospitalization in a highly unpredictable fashion as compared to patients with cutaneous burns only. As such our data illustrate the extreme importance of inhalation injury as a comorbid factor following thermal injury and reveal the present limitations for accurate quantification of the magnitude of respiratory tract injury accompanying thermal trauma.
INTRODUCTIONIn 1978, Burnstock' proposed a system for the classification of the receptors at which adenosine and adenine nucleotides act to produce their diverse and numerous effects. This proposal was based on a review of the extensive literature concerning the actions of purine nucleosides and nucleotides on a wide variety of tissues. This classification system termed the receptors at which the purine nucleosides and nucleotides act purinoceptors and proposed that there were two major subtypes, the PI-and P,purinoceptors. This classification system was based on four criteria:1. The relative potencies as agonists of adenosine, AMP, ADP, and ATP 2. The selective actions of antagonists, particularly methylxanthines such as theo-3. The activation of adenylate cyclase by adenosine but not by ATP. 4. The induction of prostaglandin synthesis by ATP but not by adenosine. ph ylline.According to this classification, P,-purinoceptors are more responsive to adenosine and AMP than to ADP and ATP. Methylxanthines such as caffeine and theophylline are selective antagonists at these P,-purinoceptors, and occupation of these receptors alters the activity of adenylate cyclase. P2-purinoceptors are more responsive to ADP and ATP than to adenosine and AMP. Methylxanthines are Classification systems for the receptors for adenosine were independently proposed by Van Calker eta[.' and Londos et al.' These classifications were based on the relative 165
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