[Metabolic Acidosis under Acetaminophen Intake - an Unordinary Side Effect]. / Metabolische Azidose unter Paracetamol ­ eine ungewöhnliche Nebenwirkung.

Metabolic acidosis is common among hospitalized patients. However, in a few cases a long-term administration of acetaminophen can lead to transient 5-oxoproline accumulation and causes metabolic acidosis with high anion gap in adults. A 73-year-old man was hospitalized with Staph. aureus sepsis after right knee prosthesis infection and received analgesic treatment with acetaminophen 2 g/d and antibiotic therapy with flucloxacillin over several weeks. The patient had a protracted course of illness and was transferred to intensive care unit with progressing vigilance reduction and for metabolic acidosis with high anion gap. Further medical investigation confirmed an increased concentration of 5-oxoproline in urine. A change in antibiotic treatment, interruption of acetaminophen and administration of acetylcysteine lead to a normalization of the acid-base balance. In a patient with metabolic acidosis under acetaminophen administration, particularly in the context of sepsis, malnutrition, liver and kidney diseases as well as antibiotic treatment with flucloxacillin an accumulation of 5-oxoproline must be considered. The treatment with acetaminophen must be interrupted and acetylcysteine should be administered.

Involvement of phosphatidylserine, alphavbeta3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages.

OBJECTIVE: Uningested dead cells may be an important source of autoantigens and may trigger autoimmune diseases such as systemic lupus erythematosus (SLE). Multiple receptors involved in the clearance of apoptotic cells have been described; however, little is known about the receptors and ligands involved in uptake of necrotic cells that release autoantigens as well. METHODS: The uptake of autologous necrotic peripheral blood lymphocytes into human monocyte-derived macrophages was qualitatively and quantitatively monitored by confocal microscopy and 2-color flow cytometry, respectively. Blocking experiments were performed to examine the receptors and molecules involved in the phagocytosis of necrotic cells. Cytokine secretion by lipopolysaccharide-activated monocytes and macrophages was determined by enzyme-linked immunosorbent assay. RESULTS: Phosphatidylserine, which was exposed on necrotic as well as apoptotic cells, promoted the recognition and removal of primary necrotic lymphocytes. Several macrophage receptor systems, including the thrombospondin-CD36-alphavbeta3 complex, CD14, and the complement component C1q, contributed to the engulfment of necrotic cells. Necrotic peripheral blood lymphocytes slightly increased the lipopolysaccharide-induced secretion of interleukin-10 and reduced the secretion of tumor necrosis factor alpha in monocytes and macrophages. CONCLUSION: Our results indicate that at least some of the receptors and adaptors mediating the uptake of apoptotic cells are also involved in the clearance of necrotic cells. Hence, necrotic cells engage phagocyte receptors such as CD36, which mediate antiinflammatory signals from apoptotic cells. Necrotic cells consequently also have the potency to provide antiinflammatory signals to phagocytes; however, these signals may be overridden by proinflammatory factors released during necrosis. These findings have implications regarding the etiopathogenesis of autoimmune diseases such as SLE, in which impaired clearance of dead cells may foster autoimmunity by the release of potential autoantigens.

Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin.

OBJECTIVE: The efficient uptake of dying cells by phagocytes is essential to the avoidance of chronic inflammation. Some human autoimmune responses are thought to be driven by autoantigens from apoptotic or necrotic cells. We analyzed the role of C1q and DNase I in the disposal of necrotic cell-derived chromatin because deficiencies in these serum factors predispose to the development of systemic autoimmune disorders, such as systemic lupus erythematosus. METHODS: Human necrotic peripheral blood lymphocytes were incubated in cell culture medium supplemented with various sera or serum components. Chromatin degradation was monitored by measuring the residual DNA content by flow cytometry. The uptake of necrotic cell-derived nuclei was analyzed by in vitro phagocytosis assays. RESULTS: Reconstitution of C1q-depleted serum with C1q strongly increased its ability to degrade necrotic cell-derived chromatin. Although C1q itself displayed no DNase activity, it strongly augmented the activity of serum DNase I. Whereas an excess of recombinant DNase I degraded chromatin in the absence of C1q, efficient uptake of the predigested material by monocyte-derived phagocytes required the presence of C1q. These data show that C1q and DNase I cooperate in the degradation of chromatin from necrotic cells. Furthermore, C1q was found to be necessary for effective uptake of degraded chromatin by monocyte-derived phagocytes. CONCLUSION: C1q or DNase I deficiencies may precipitate autoimmunity in humans by a mechanism similar to that of other molecules that are involved in the safe, efficient, and rapid disposal of dying cells.