Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of Inlammator dimseas, but sg t side effects such as g oi l erosion and renal damage lmit their use. NSAIDs Inhibit the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to p (PGs) and thromboxane. Two forms of COX have been identlfled-COX-1, which is constitutively expressed in most tissues and organs, and the Inducible enzyme, COX-2, whih has been localized primarily to ilmmatory cells and tsues. In an animal model of acute inflammation (Injection ofcarrageenan into the footpad), edema was produced that was associated with marked accumulation of COX-2 mRNA and thromboxane. A selective inhibitor of COX-2 (SC-58125) inhibited edema at the inmatory site and was analgesic but had no effect on PG production In the stomach and did not cause gastric toxicity. These data suggest that selective inhibition of COX-2 may produce superior an mmatory drugs with substantial safety advantages over existing NSAIDs. bone density, fluid and electrolyte imbalance, and "Cushinglike" symptoms. These untoward effects limit glucocorticoid use in chronic inflammatory disorders such as rheumatoid arthritis (13).Studies were designed to evaluate the role ofCOX-2 in vivo at the site of inflammation. We report that in a model of inflammation useful in the characterization of NSAIDs, the carrageenan-injected rat paw, COX-2 was expressed locally in response to the proinflammatory stimulus and that the induction of COX-2 mRNA coincided with the synthesis of proinflammatory PGs and the development of edema and hyperalgesia. COX-1 mRNA was detectable in the normal rat paw, but its expression did not change following the onset of the inflammatory reaction. Furthermore, a selective inhibitor of COX-2 {SC-58125: 1-[(4-methylsulfonyl)phenyll-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole} blocked edema and hyperalgesia in vivo following an inflammatory insult, without causing gastric mucosal damage.

We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammaion in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by hih levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of COX-2 mRNA and protein coincided with the production of PGs in the pouch tissue and cellular infiltrate. Carrageenan-induced COX-2 immunoreactivity was localized to macrophages obtained from the fluid exudate as well as to the inner surface layer of cells within the pouch lining. Dexamethasone inhibited both COX-2 expression and PG synthesis in the fluid exudate but failed to inhibit PG synthesis in the stomach. Furthermore, NS-398, a selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, blocked proinflammatory PG synthesis in the air pouch. In contrast, only indomethacin blocked gastric PG and, additionally, produced gastric lesions. These results suggest that inhibitors of COX-2 are potent antiinflammatory agents which do not produce the typical side effects (e.g., gastric ulcers) associated with the nonselective, COX-1-direc antiinfla tory drugs.Nonsteroidal antiinflammatory drugs (NSAIDs) are used to treat acute and chronic inflammatory disorders such as rheumatoid arthritis. The antiinflammatory mechanism of NSAIDs is due to a reduction ofprostaglandin (PG) synthesis by the direct inhibition of cyclooxygenase (COX; prostaglandin-endoperoxide synthase, EC 1.14.99.1) (1). Unfortunately, inhibition of PG production in organs such as stomach and kidney can result in gastric lesions, nephrotoxicity, and increased bleeding.COX exists in two forms. COX-1 is in most tissues and is involved in the physiological production of PGs. COX-2 is cytokine-inducible and is expressed in inflammatory cells (2-9). The identification of constitutive and inducible COX enzymes led to the hypothesis that COX-2 is primarily responsible for PGs produced in inflammation and COX-1 for PGs involved in normal homeostasis (4-6, 10, 11).The rat air pouch is a convenient model to study acute inflammation (12). It is formed by the subcutaneous injection of air over several days and is composed of a lining of cells that consists primarily of macrophages and fibroblasts. Injection of carrageenan into the fully formed air pouch produces an inflammatory granulomatous reaction characterized by a marked production of biochemical mediators in the fluid exudate, including PGs and leukotrienes, as well as a significant influx of polymorphonuclear leukocytes (PMNs) and macrophages (13). Using molecular and pharmacological reagents, we studied the role of COX-2 in this model of inflammation by specific examination of the induction of COX-2 mRNA and protein as well as the production of PGs in the pouch exudate. The results indicate that induction of COX-2 is responsible for the production of PGs at the site of inflammation, whereas the normal synthesis of PGs in the stomach appears to depend on constitutive...

Wingless (Wnt) is a potent morphogen demonstrated in multiple cell lineages to promote the expansion and maintenance of stem and progenitor cell populations. Wnt effects are highly context dependent, and varying effects of Wnt signaling on hematopoietic stem cells (HSCs) have been reported. We explored the impact of Wnt signaling in vivo, specifically in the context of the HSC niche by using an osteoblast-specific promoter driving expression of the paninhibitor of canonical Wnt signaling, Dickkopf1 (Dkk1). Here we report that Wnt signaling was markedly inhibited in HSCs and, unexpectedly given prior reports, reduction in HSC Wnt signaling resulted in reduced p21Cip1 expression, increased cell cycling, and a progressive decline in regenerative function after transplantation. This effect was microenvironment determined, but irreversible if the cells were transferred to a normal host. Wnt pathway activation in the niche is required to limit HSC proliferation and preserve the reconstituting function of endogenous hematopoietic stem cells.

Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system.

Angiogenesis is the process by which new blood vessels are formed. This process supports normal physiology as well as contributes to progression of disease. Progressive rheumatoid arthritis and growth of tumors are two pathologies to which angiogenesis contributes. In arthritis, we know that prostaglandins (PGs) and the enzyme cyclooxygenase-2, which catalyses prostaglandin production, are inflammatory mediators. These mediators are involved in rheumatoid arthritis and cancer-induced angiogenic processes. We discuss, herein, recent findings on the expression of cyclooxygenases in both rheumatoid arthritis and human cancer, and the links between COX-2, PGs, and angiogenesis. We also propose a model for the possible mechanistic interaction of the various cell types involved in angiogenesis.