Inflammation and the resulting accumulation of reactive oxygen species (ROS) play an important role in the intrinsic and photoaging of human skin in vivo. Environmental insults such as ultraviolet (UV) rays from sun, cigarette smoke exposure and pollutants, and the natural process of aging contribute to the generation of free radicals and ROS that stimulate the inflammatory process in the skin. UV irradiation initiates and activates a complex cascade of biochemical reactions in human skin. In short, UV causes depletion of cellular antioxidants and antioxidant enzymes (SOD, catalase), initiates DNA damage leading to the formation of thymidine dimmers, activates the neuroendocrine system leading to immunosuppression and release of neuroendocrine mediators, and causes increased synthesis and release of pro-inflammatory mediators from a variety of skin cells. The pro-inflammatory mediators increase the permeability of capillaries leading to infiltration and activation of neutrophils and other phagocytic cells into the skin. The net result of all these effects is inflammation and free radical generation (both reactive oxygen and nitrogen species). Furthermore, elastsases and other proteases (cathepsin G) released from neutrophils cause further inflammation, and activation of matrix metalloproteases. The inflammation further activates the transcription of various matrixes degrading metalloproteases, leading to abnormal matrix degradation and accumulation of non-functional matrix components. In addition, the inflammation and ROS cause oxidative damage to cellular proteins, lipids and carbohydrates, which accumulates in the dermal and epidermal compartments, contributing to the aetiology of photoaging. Strategies to prevent photodamage caused by this cascade of reactions initiated by UV include: prevention of UV penetration into skin by physical and chemical sunscreens, prevention/reduction of inflammation using anti-inflammatory compounds (e.g. cyclooxygenase inhibitors, inhibitors of cytokine generation); scavenging and quenching of ROS by antioxidants; inhibition of neutrophil elastase activity to prevent extracellular matrix damage and activation of matrix metalloproteases (MMPs), and inhibition of MMP expression (e.g. by retinoids) and activity (e.g. by natural and synthetic inhibitors).

Ultraviolet radiation and skin aging: roles of reactive oxygen species, inflammation and protease activation, and strategies for prevention of inflammation-induced matrix degradation – a review

A method for inhibiting the activity of serine proteinase in biological systems includes administering to the system a serine proteinase inhibitory amount of a hydrophobic 4-de(dimethylamino) tetracycline. The method reduces tissue destruction during inflammation resulting from the activity of human leukocyte elastase. The method is used for pharmaceutical and cosmetic purposes.

Serine proteinase inhibitory activity by hydrophobic tetracycline

This invention provides a method for identifying complexes from a library, wherein said complexes are selected for their ability to perform a preselected or desired function on a target molecule or by having a preselected structure, each complex being designated a morphatide, said method comprising: (a) preparing a library of morphatides, comprised of: (i) a scaffolding nucleic acid having one or more regions or randomized sequence; (ii) linker components; and (iii) agent molecules; (b) screening the library of morphatides prepared in step (a) by contacting, binding, or associating the morphatides with suitable target molecules; (c) separating the morphatides from the library of morphatides and target molecules; thereby identifying complexes selected for their ability to perform a preselected or desired function on a target molecule or by having a preselected structure.

Morphatides: novel shape and structure libraries

Publisher Summary This chapter discusses the inhibition strategies published over the past two years and the current status of proteinases released by neutrophils and mononuclear phagocytes. Neutrophils, when activated, release a complex assortment of agents that can destroy normal cells and dissolve connective tissues. Lysosomal cysteine proteinases, with pH optima in the acid range and three neutral swine proteinases, elastase, cathepsin G, and protinase-3, are stored in the azurophil granules. Two metalloproteinases, collagenase, and gelatinase are found in specific secondary and tertiary granules, respectively. In contrast to neutrophils, macrophages are long-lived cells, with important synthetic capabilities and major secretory activities, and with a remarkable potential for functional differentiation. Macrophages lack sub-cellular storage organelles comparable to neutrophil granules and do not contain serine proteinases. Proteinases must perform their normal functions during homeostasis, as well as disease-related tissue destruction, in settings ostensibly dominated by high concentrations of powerful endogenous inhibitors (anti-proteinases) that can rapidly and irreversibly inhibit proteinase activity in plasma and interstitial fluids. Triggered neutrophils have the ability to create a subjacent sequestered environment from which endogenous inhibitors are excluded and released proteinases can act unmolested. Interleukin-1β (IL-1β) is a major mediator of inflammation and potent bone resorptive cytokine that also mediates soft tissue destruction through the stimulation of prostaglandin production and the induction of collagenase and other proteinases. At least nine distinct members of the matrixin family, produced by connective tissue cells, have been identified and broadly subdivided into three categories on the basis of substrate specificity: the collagenases, gelatinases, and stromelysins. Matrix metalloproteinases (MMPs) are all Zn 2+ and Ca 2+ requiring enzymes that are secreted in inactive proforms, activated by loss of a propeptide of molecular weight -10,000, and then subject to inhibition by tissue inhibitor of metalloproteinase (TIMP)-1 or -2. These enzymes have the combined ability to degrade all the components of the extracellular matrix. Despite the many potent in vitro inhibitors, very few orally bioavailable proteinase inhibitors have been reported and evaluated in a clinical setting targeted for inflammatory diseases.

Chapter 20. Proteinases in Inflammation

We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inhibitors of human leukocyte elastase (HLE). The enzyme inhibition is regulated by the size of the oligomer, as well as, the number of charges. Lipophilicity is an important element in determining potency and specificity against other basic enzymes. Compounds whose scaffolds contain three phenoxyacetic acid groups and three alkyl ethers are competitive and specific inhibitors of HLE with Ki = 20 nM. The mechanism of action of this class of compounds is believed to involve multidendate interactions with the surface of HLE near the active site which prevents substrate access to the catalytic site.

Anionic- and Lipophilic-Mediated Surface Binding Inhibitors of Human Leukocyte Elastase

We have recently described the inhibition of human neutrophil elastase (HNE) by RNA purified from Streptococcus pneumoniae (1). Inhibition of this enzyme by a wide variety of polyanions has also been reported by others. Such agents include ribonucleic acids from yeast (1,2), E. coli (2), polyribosylribitol phosphate from H. influenzae capsules (1), and several sulfated polysaccharides (3-5). In addition to these naturally-occuring polyanions, synthetic RNA homopolymers were also tested previously (2).

Inhibition of human neutrophil elastase by polyguanylic acid and other synthetic polynucleotides.

Synthesis and evaluation of CE-0266: A new human neutrophil elastase inhibitor

Animal models are often used to identify aspects of the pathophysiology and to develop new therapeutic interventions for human disorders. Leukocyte serine elastases are key mediators of inflammation and meaningful therapeutic targets because of their potential contributions to the Acute Respiratory Distress Syndrome (ARDS) and other inflammatory disorders. We compared the extracellular matrix degrading and bactericidal activities against both Escherichia coli and Staphylococcus aureus, of leukocytes from humans, dogs, hamsters, rats, pigs and rabbits before and after adding highly selective serine elastase inhibitors. Not surprisingly, we found significant species-dependent differences in both activities and the responses to adding serine elastase inhibitors. Our results reinforce the need for care in selecting the optimal animal species for evaluating both the underlying pathophysiology of inflammatory diseases and potential new interventions being developed to treat these conditions.

/pdf/disparate-species-dependent-leukocyte-behavior-before-and-453as937zu.pdf

Disparate Species-Dependent Leukocyte Behavior before and after Addingan Elastase Inhibitor

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Inhibition of human neutrophil elastase by polyguanylic acid and other synthetic polynucleotides.

Synthesis and evaluation of CE-0266: A new human neutrophil elastase inhibitor

Disparate Species-Dependent Leukocyte Behavior before and after Addingan Elastase Inhibitor