Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI) leads to impaired wound healing due to enhanced activity of TGFbeta and perhaps additional mechanisms. Proepithelin (PEPI), an epithelial growth factor, can be converted to epithelins (EPIs) in vivo by unknown mechanisms with unknown consequences. We found that PEPI and EPIs exert opposing activities. EPIs inhibit the growth of epithelial cells but induce them to secrete the neutrophil attractant IL-8, while PEPI blocks neutrophil activation by tumor necrosis factor, preventing release of oxidants and proteases. SLPI and PEPI form complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrects the wound-healing defect in SLPI null mice. Thus, SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing.

No abstract

N-Arylanthranilic acids, known generically as the fenamates, are nonsteroidal antiinflammatory drugs (NSAIDs) that block the metabolism of arachidonic acid by the enzyme cyclooxygenase (CO). Substitution of the carboxylic acid functionality of several fenamates with acidic heterocycles provided dual inhibitors of CO and 5-lipoxygenase (5-LO) activities when tested in an intact rat basophilic leukemia (RBL-1) cell line. Compound 5b (IC50 = 0.77 microM (5-LO), 0.27 microM (CO)) which contains an 1,3,4-oxadiazole-2-thione replacement and 10b (IC50 = 0.87 microM (5-LO), 0.85 microM (CO)) which contains a 1,3,4-thiadiazole-2-thione are the most potent inhibitors of 5-LO and CO activities from these series. Both of these heterocyclic analogs of flufenamic acid are also active in carageenin-induced rat footpad edema (CFE), a model of acute inflammation. When dosed orally the ID50s for 5b and 10b in CFE are 8.5 and 4.7 mg/kg, respectively.

A variety of benzylideneoxazoles, -thiazoles, and -imidazoles derived from 2,6-di-tert-butylphenol were prepared and evaluated as dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia (RBL-1) cells. The target compounds exhibit varying degrees of selectivity toward the two enzymes. Several compounds are orally active in the rat carageenan footpad edema (CFE) and mycobacterium footpad edema (MFE) antiinflammatory models. Structure-activity relationships are discussed. From this work, (Z)-5-[[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-methylene]-2-imino-4-thiazolidinone methanesulfonate salt (CI-1004) was identified as a potent dual inhibitor of 5-lipoxygenase (IC50 = 0.77 microM) and cyclooxygenase (IC50 = 0.39 microM), with oral activity (ID40 = 0.6 mg/kg) in the rat MFE model of inflammation.

Serum SLPI is elevated in human sepsis and experimental endotoxemia. Maximal concentrations of serum SLPI correlate significantly with maximal multiple organ dysfunction scores in patients with sepsis. Secretory leukocyte protease inhibitor may function to limit ongoing neutrophil-mediated tissue injury associated with organ dysfunction.