Proinflammatory kupffer cell alterations after femur fracture trauma and sepsis in rats.

This study examined effects of trauma and sepsis on Kupffer cell function. When CBA/J mice had femur fracture (FFx), no deaths occurred. After cecal ligation and puncture (CLP), 44% died. Following combined injuries (FFx + CLP), mortality increased to 60%, suggesting a deleterious effect between FFx + CLP. Kupffer cell ablation with GdCI3 decreased mortality to 13% after CLP and 5% after FFx + CLP. After FFx, CLP, and FFx + CLP, Kupffer cells isolated from Sprague-Dawley rats produced 720%, 1,100%, and 2,130% more O2. than sham, respectively. Phagocytosis increased 320%, 610%, and 150%. Kupffer cell PGE2 production also increased 300%, 510%, and 300% over sham. After FFx alone, TNF-alpha production decreased 40%. By contrast, CLP and FFx + CLP increased TNF-alpha release 25% and 100%, respectively. After FFx, NO. production decreased 44%, whereas NO increased 280% and 260% after CLP and FFx + CLP. These findings indicate that Kupffer cells mediate mortality after CLP and FFx + CLP. Increased mortality is associated with a more proinflammatory and less antimicrobial Kupffer cell phenotype.

Adaptive Kupffer cell alterations after femur fracture trauma in rats.

Because Kupffer cells constitute the largest fixed macrophage population and reside at a strategic position in hepatic sinusoids, interacting with hepatocytes, circulating cells, and mediators from the gut, they may be important in the inflammatory response after injury. This study examined the effect of remote tissue injury on Kupffer cell function. Femurs of Sprague-Dawley rats were fractured under anesthesia. Subsequently, their livers were perfused for measurement of oxygen consumption and the isolation and culture of Kupffer cells. At 2 and 48 h after femur fracture, hepatic oxygen consumption increased 17 and 19%, respectively. Gadolinium chloride pretreatment to ablate Kupffer cells blocked this increase of hepatic oxygen consumption after femur fracture but had no effect in sham-operated animals. In Kupffer cells isolated and cultured 2 h after femur fracture, superoxide formation stimulated by phorbol ester increased eightfold, phagocytosis increased fourfold, and lipopolysaccharide (LPS)-stimulated prostaglandin E2 increased sixfold in comparison to sham-operated controls. In contrast, LPS-stimulated tumor necrosis factor-alpha and nitric oxide production decreased 50 and 60%, respectively. These data show that peripheral trauma rapidly induces changes in hepatic macrophages characterized by adaptation to a more antimicrobial and less proinflammatory phenotype.

An in vitro investigation into the effects of repetitive motion and nonsteroidal antiinflammatory medication on human tendon fibroblasts.

Soft tissue injuries due to repetitive motion are common sports injuries and are often treated with antiinflammatory therapies. We investigated the in vitro effects of repetitive motion and nonsteroidal antiinflammatory medication on human tendon fibroblasts. In addition, we studied the effects related to the presence of inflammatory cells. Repetitive motion was associated with an increased release of prostaglandin E2 and increased deoxyribonucleic acid (DNA) and protein synthesis. The presence of nonsteroidal antiinflammatory medication decreased prostaglandin E2 release and DNA synthesis but increased protein synthesis. Contact with macrophages caused a marked additional increase in prostaglandin E2 and a concomitant increase in DNA synthesis. Release of interleukin-6 by the macrophages also suggested that this cytokine plays a role in the response to repetitive motion. Our results can aid in the search for a more scientific approach to the treatment of soft tissue injuries associated with repetitive motion. They suggest that nonsteroidal antiinflammatory medication may have potentially negative effects during the proliferative phase of a healing since it was associated with decreased DNA synthesis. However, it may be beneficial in the maturation and remodeling phase since it stimulated protein synthesis.