Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4473_Библиотеки_им_академика_М_И_Перельмана

Heparin is a glycosaminoglycan and remains one of the most important anticoagulant drugs in clin­ical practice. Heparin binds to antithrombin and accelerates the inhibitory activity to thrombin, FXa, and other coagulation factors. It is well known that heparin possesses a wide variety of anti-inammatory activities, including inhibition of inammatory mediators, suppression of lym­phocyte, neutrophil, and eosinophil functions, and inhibition of mast cell degranulation [58–60]. Heparin plays regulatory roles in airway inam­mation and subsequent tissue remodeling by binding nonspecically to many proteins involved in the inammation process, including cytokines, growth factors, adhesion molecules, tissue destructive enzymes, complement factors, and extracellular matrix proteins [55]. Inhaled hepa­rin attenuates antigen-induced airway hyperreac­tivity in asthmatic rats [61] and sheep [62], and it inhibits smoke-induced lung injury in sheep [63]. Heparin also attenuates nasal airway pressure and cellular inltration in nasal lavage uids in a guinea pig model of AR [64]. Several clinical studies have shown the anti-inammatory effects of inhaled heparin or nebulized heparin in patients with bronchial asthma and AR, and no adverse effects such as bleeding or thrombocyto­penia have been reported [59, 65–69].

The anti-inammatory effects of heparin on rat nasal epithelium are examined using LPS- or antigen-induced inammation. Intranasal instil­lation of heparin attenuates LPS-induced neutro­phil inltration, goblet cell metaplasia, and mucus production in rat nasal epithelium, and the low-molecular weight heparin (LMWH), enoxa­parin, shows similar inhibitory effects on LPS­induced changes as those of heparin [70]. LMWH is a fragment of heparin produced by controlled chemical and enzymatic degradation, and its binding to antithrombin accelerates its anticoagu­lant activity. LMWH has a longer half-life and better bioavailability caused by the reduced bind­ing to plasma proteins and endothelium. LMWH also attenuates antigen-induced neutrophil/eosin­ophil inltration, goblet cell metaplasia, and

APC generation is decreased in the lungs of patients with airway inammation, such as bron­chial asthma and lung brosis, and reduced APC function is associated with enhanced collagen formation in the lungs of patients with lung bro­sis [75–77]. Intratracheal administration of APC inhibits bleomycin-induced lung brosis and pro­duction of PDGF, TNF-α, and IL-6in the mouse lung, and anti-EPCR antibody suppresses these inhibitory activities of APC [57]. Inhaled APC attenuates antigen-induced eosinophil inltra­tion, Th2 cytokine production, and airway hyper­reactivity in mouse lung, and anti-EPCR antibody suppresses these inhibitory activities [14].

Intranasal instillation of APC inhibits thrombin­induced goblet cell metaplasia and mucus production in rat nasal epithelium, and APC inhibits TNF-α or epidermal growth factor (EGF)-induced secretion of MUC5AC mucin from cultured airway epithelial cells [1]. APC inhibits thrombin-induced production of PDGF from cultured airway epithelial cells and from macrophages. EPCR is also expressed in airway epithelial cells and macrophages, and the inhibi­tory effects of APC on PDGF production are sup­pressed by anti-EPCR antibody [57]. APC also inhibits the chemotactic activity of eosinophils, neutrophils, and lymphocytes through the EPCR [78–80]. These results show that reduced activi­ties of the protein C system contribute to the pathophysiology of airway inammation, and APC has a variety of anti-inammatory activities through its own receptor EPCR on airway epithe­lial cells, macrophages, and leukocytes. Topical administration of APC may have therapeutic potential for the treatment of intractable rhinosinusitis.