Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases.

Unità Operativa di Dermatologia, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Dipartimento di Anestesiologia, Terapia Intensiva e Scienze Dermatologiche, Università degli Studi di Milano, Milano, Italy.
Clinical & Experimental Immunology (Impact Factor: 3.41). 10/2010; 162(1):100-7. DOI: 10.1111/j.1365-2249.2010.04201.x
Source: PubMed

ABSTRACT Pyoderma gangrenosum (PG) is a rare, immune-mediated inflammatory skin disease presenting with painful ulcers having undermined edges. Less commonly, bullous and vegetative variants exist. Histology consists of a neutrophil-rich dermal infiltrate. We characterized immunohistochemically the infiltrate in different variants of PG and in another neutrophilic dermatosis as Sweet's syndrome. We studied 21 patients with PG, eight with Sweet's syndrome and 20 controls, evaluating skin immunoreactivity for inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17], metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF). Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-α, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in both PG and Sweet's syndrome than in controls (P=0·0001). Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome (P=0·008-P=0·0001). In ulcerative PG, the expression of CD3 (panT cell marker) and CD163 (macrophage marker) were significantly higher in wound edge than wound bed (P=0·0001). In contrast, the neutrophil marker myeloperoxidase was expressed more significantly in wound bed than wound edge (P=0·0001). Our study identifies PG as a paradigm of neutrophil-mediated inflammation, with proinflammatory cytokines/chemokines and MMPs acting as important effectors for the tissue damage, particularly in ulcerative and bullous PG where damage is stronger. In ulcerative PG, the wound bed is the site of neutrophil-recruitment, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation.

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    ABSTRACT: Introduction Pyoderma gangrenosum (PG) is a rare sterile neutrophilic dermatosis characterized by painful recurrent ulcerations. It is frequently associated with inflammatory bowel disease, rheumatoid arthritis, or malignancies. PG is a diagnosis of exclusion, and it is based on clinical presentation, histology, history of an underlying disease, and exclusion of other causes of ulceration. Case Report The authors report a 62-year-old male who developed a nonhealing ulcer at the site of incision following nephrectomy for renal cell carcinoma. Past medical history included chronic lymphocytic leukemia treated with rituximab. Histology of the skin lesion showed a phlegmonous nonspecific inflammation without being able to differentiate between a necrotizing wound infection and PG. The patient’s condition was initially diagnosed as an infectious process and treated accordingly. After unsuccessful results with systemic antibiotics, high-dose corticosteroids induced prompt healing of the wound. On these bases, the diagnosis of postoperative PG within chronic lymphocytic leukemia and renal cell carcinoma was made. Conclusion Faced with postoperative necrotizing ulceration resistant to correctly administered antibiotics, PG must be considered. In such condition, the diagnosis must not be guided primarily by histology and early advice of a dermatologist is recommended.
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    ABSTRACT: Pyoderma gangrenosum (PG) and Sweet’s syndrome (SS) are skin diseases usually presenting with recurrent ulcers and erythematous plaques, respectively. The accumulation of neutrophils in the skin, characteristic of these conditions, led to coin the term of neutrophilic dermatoses to define them. Recently, neutrophilic dermatoses have been included in the group of autoinflammatory diseases, which classically comprises genetically determined forms due to mutations of genes regulating the innate immune response. Both PG and SS are frequently associated with inflammatory bowel diseases (IBDs); however, IBD patients develop PG in 1–3 % of cases, whereas SS is rarer. Clinically, PG presents with deep erythematous-to-violaceous painful ulcers with well-defined borders; bullous, pustular, and vegetative variants can also occur. SS is characterized by the abrupt onset of fever, peripheral neutrophilia, tender erythematous skin lesions, and a diffuse neutrophilic dermal infiltrate. It is also known as acute febrile neutrophilic dermatosis. Treatment of PG involves a combination of wound care, topical medications, antibiotics for secondary infections, and treatment of the underlying IBD. Topical therapies include corticosteroids and the calcineurin inhibitor tacrolimus. The most frequently used systemic medications are corticosteroids and cyclosporine, in monotherapy or in combination. Dapsone, azathioprine, cyclophosphamide, methotrexate, intravenous immunoglobulins, mycophenolate mofetil, and plasmapheresis are considered second-line agents. Hyperbaric oxygen, as supportive therapy, can be added. Anti-TNF-α agents such as etanercept, infliximab, and adalimumab are used in refractory cases. SS is usually responsive to oral corticosteroids, and the above-mentioned immunosuppressants should be considered in resistant or highly relapsing cases.
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    ABSTRACT: Chronic urticaria (CU) is a cutaneous disease characterized by the recurrent eruption of short-lived wheals for at least six weeks. The wheals, which are surface swelling of the dermis accompanied by itching, may be elicited by different stimuli, or occur spontaneously. The pathogenesis of spontaneous CU has long remained a mystery, with food allergy, intolerance to food additives and chronic infections having been indicated as the main causes of the disease. The demonstration of histamine releasing autoantibodies in the serum of CU patients led to consider it of autoimmune origin in about 45 % of cases, this condition being “idiopathic” in the remaining 55 %. We recently evaluated the possible involvement of blood coagulation in its pathophysiology by measuring in CU patients the plasma levels of prothrombin fragment F1 + 2, a polypeptide released into the circulation during the activation of prothrombin to thrombin, and D-dimer, a marker of fibrin lysis. Interestingly, both F1 + 2 and D-dimer plasma levels were extremely high during the acute phase of disease, but were completely normal after remission, paralleling urticaria severity. It is noteworthy that thrombin causes an increase in vascular permeability, thus amplifying the CU inflammatory network. Moreover, immunohistochemical studies showed expression of tissue factor, the main initiator of coagulation, in CU skin lesions, and co-localization experiments demonstrated that tissue factor is expressed by eosinophils in the inflammatory infiltrate. All these findings support that coagulation activation contributes in the pathophysiology of spontaneous CU, and provide the rationale for using also anticoagulant and antifibrinolytic agents to treat it.
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