The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

Staphylococcus aureus is a major human pathogen interfering with host-cell functions. Impaired wound healing is often observed in S aureus-infected wounds, yet, the underlying mechanisms are poorly defined. Here, we identify the extracellular adherence protein (Eap) of S aureus to be responsible for impaired wound healing. In a mouse wound-healing model wound closure was inhibited in the presence of wild-type S aureus and this effect was reversible when the wounds were incubated with an isogenic Eap-deficient strain. Isolated Eap also delayed wound closure. In the presence of Eap, recruitment of inflammatory cells to the wound site as well as neovascularization of the wound were prevented. In vitro, Eap significantly reduced intercellular adhesion molecule 1 (ICAM-1)-dependent leukocyte-endothelial interactions and diminished the consequent activation of the proinflammatory transcription factor nuclear factor B (NFB) in leukocytes associated with a decrease in expression of tissue factor. Moreover, Eap blocked ␣ v -integrin-mediated endothelial-cell migration and capillary tube formation, and neovascularization in matrigels in vivo. Collectively, the potent anti-inflammatory and antiangiogenic properties of Eap provide an underlying mechanism that may explain the impaired wound healing in S aureus-infected wounds. Eap may also serve as a lead compound for new antiinflammatory and antiangiogenic therapies in several pathologies. IntroductionStaphylococcus aureus, and especially strains with resistance to antimicrobial agents, is an unabated challenge in communityacquired and nosocomial infections ranging from wound infections or osteomyelitis to life-threatening endocarditis, or septic shock. 1,2 Wound infection with S aureus is frequently associated with impaired healing; yet, interference of S aureus with wound-healing mechanisms is poorly understood. 3,4 S aureus expresses a number of bacterial cell wall-anchored adhesins mediating its adherence to host extracellular matrix (ECM) components. 5 Moreover, S aureus produces and secretes proteins with ECM binding properties, such as coagulase, 6 the extracellular fibrinogen binding protein, 5 as well as Eap, also designated Map (major histocompatibility [MHC] class II analogous protein), a 60-kDa protein with a broad repertoire of interactions to host ECM components. [7][8][9] Recently, we demonstrated direct interactions of Eap with the host adhesive proteins intercellular adhesion molecule 1 (ICAM-1), fibrinogen (FBG), and vitronectin (VN), resulting in the disruption of integrin-dependent leukocyte recruitment in vitro and in vivo, thereby serving as a potent anti-inflammatory factor. 10 While Eap was also shown to exert immunomodulatory actions by interfering with T-cell functions, 11 a possible interference of Eap with host wound healing is not defined.Wound healing is a well-organized sequence of events involving inflammatory, proliferative, and maturation phases. 12,13 (1) The inflammatory phase requires initial recruitment of neutrophils and later of ma...

Since cations have been reported as essential regulators of biofilm, we investigated the potential of the broad-spectrum antimicrobial and cation-chelator nitroxoline as an antibiofilm agent. Biofilm mass synthesis was reduced by up to 80% at sub-MIC nitroxoline concentrations in Pseudomonas aeruginosa, and structures formed were reticulate rather than compact. In preformed biofilms, viable cell counts were reduced by 4 logs at therapeutic concentrations. Complexation of iron and zinc was demonstrated to underlie nitroxoline's potent antibiofilm activity.

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