Hypoxia serves as a physiological cue to drive angiogenic response via HIF-dependent mechanisms. Interestingly, minor elevation of lactate levels in the tissue produces the same effect under aerobic conditions. Aerobic glycolysis contributes to lactate accumulation in the presence of oxygen especially under inflammatory conditions. We have previously postulated that aerobic lactate accumulation, already known to stimulate collagen deposition, will also stimulate angiogenesis. If substantiated, this concept would advance understanding of wound healing and aerobic angiogenesis because lactate accumulation has many aerobic sources. In this study, Matrigel® plugs containing a powdered, hydrolysable lactate polymer were implanted into the subcutaneous space of mice. Lactate monomer concentrations in the implant were consistent with wound levels for over 11 days. They induced little inflammation but considerable VEGF production and were highly angiogenic as opposed to controls. Arterial hypoxia abrogated angiogenesis. Furthermore, inhibition of lactate dehydrogenase using oxamate also prevented the angiogenic effects of lactate. Lactate monomer, at concentrations found in cutaneous wounds, stabilized HIF-1α and increased VEGF levels in aerobically cultured human endothelial cells. Accumulated lactate, therefore, appears to convey the impression of “metabolic need” for vascularization even in well-oxygenated and pH-neutral conditions. Lactate and oxygen both stimulate angiogenesis and matrix deposition.

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

During phagocytosis, phagocytic cells generate superoxide and other reactive oxygen species, which are involved in antibacterial activity. However, many bacteria possess antioxidant defenses that may explain their survival in inflammatory foci. These defenses include antioxidant enzymes such as superoxide dismutase and catalase, DNA repair systems, scavenging substrates, and competition with phagocytes for molecular oxygen. These defenses are probably coordinated, and different responses occur with different reactive oxygen species. Escherichia coli and Salmonella typhimurium mutants have allowed the demonstration of a variety of critical genes for enzymatic defense and DNA repair, as well as an oxyR regulon system. In more complex systems, the conditions found in inflammatory foci, such as decreasing glucose and the production of lactate, enhance bacterial catalase production and resistance to hydrogen peroxide. Resistance and adaptation to phagocyte-derived oxidant stress are critical aspects of bacterial pathogenesis.

Bacterial adaptation to oxidative stress: implications for pathogenesis and interaction with phagocytic cells.

Defenses against oxidative stress are crucial for the survival of the pathogens Neisseria meningitidis and Neisseria gonorrhoeae. An Mn(II) uptake system is involved in manganese (Mn)-dependent resistance to superoxide radicals in N. gonorrhoeae. Here, we show that accumulation of Mn also confers resistance to hydrogen peroxide killing via a catalase-independent mechanism. An mntC mutant of N. meningitidis is susceptible to oxidative killing, but supplementation of growth media with Mn does not enhance the organism's resistance to oxidative killing. N. meningitidis is able to grow in the presence of millimolar levels of Mn ion, in contrast to N. gonorrhoeae, whose growth is retarded at Mn concentrations >100 mmol/L, indicating that Mn homeostasis in the 2 species is probably quite different. N. meningitidis superoxide dismutase B plays a role in protection against oxidative killing. However, a sodC mutant of N. meningitidis is no more sensitive to oxidative killing than is the wild type. A cytochrome c peroxidase (Ccp) is present in N. gonorrhoeae but not in N. meningitidis. Investigations of a ccp mutant revealed a role for Ccp in protection against hydrogen peroxide killing. These differences in oxidative defenses in the pathogenic Neisseria are most likely a result of their localization in different ecological niches.

Defenses against oxidative stress in Neisseria gonorrhoeae and Neisseria meningitidis: distinctive systems for different lifestyles.

Symptomatic infection with Neisseria gonorrhoeae (Gc) results in a potent polymorphonuclear leukocyte (PMN)-driven inflammatory response, but the mechanisms by which Gc withstands PMN attack are poorly defined. Here we report that Gc can suppress the PMN oxidative burst, a central component of the PMN antimicrobial arsenal. Primary human PMNs remained viable after exposure to liquid-grown, exponential-phase, opacity-associated protein (Opa)-negative Gc of strains FA1090 and MS11 but did not generate reactive oxygen species (ROS), even after bacterial opsonization. Liquid-grown FA1090 Gc expressing OpaB, an Opa protein previously correlated with PMN ROS production, elicited a minor PMN oxidative burst. PMN ROS production in response to Opa(-) and OpaB+ Gc was markedly enhanced if bacteria were agar-grown or if liquid-grown bacteria were heat-killed. Liquid-grown Opa(-) Gc inhibited the PMN oxidative burst elicited by isogenic dead bacteria, formylated peptides or Staphylococcus aureus but did not inhibit PMN ROS production by OpaB+ Gc or phorbol esters. Suppression of the oxidative burst required Gc-PMN contact and bacterial protein synthesis but not phagocytosis. These results suggest that viable Gc directly inhibits PMN signalling pathways required for induction of the oxidative burst, which may contribute to gonococcal pathogenesis during inflammatory stages of gonorrhoeal disease.

/pdf/neisseria-gonorrhoeae-suppresses-the-oxidative-burst-of-28te3ptrho.pdf

Neisseria gonorrhoeae suppresses the oxidative burst of human polymorphonuclear leukocytes

Infection with the human-specific bacterial pathogen Neisseria gonorrhoeae triggers a potent, local inflammatory response driven by polymorphonuclear leukocytes (neutrophils or PMNs). PMNs are terminally differentiated phagocytic cells that are a vital component of the host innate immune response and are the first responders to bacterial and fungal infections. PMNs possess a diverse arsenal of components to combat microorganisms, including the production of reactive oxygen species and release of degradative enzymes and antimicrobial peptides. Despite numerous PMNs at the site of gonococcal infection, N. gonorrhoeae can be cultured from the PMN-rich exudates of individuals with acute gonorrhea, indicating that some bacteria resist killing by neutrophils. The contribution of PMNs to gonorrheal pathogenesis has been modeled in vivo by human male urethral challenge and murine female genital inoculation and in vitro using isolated primary PMNs or PMN-derived cell lines. These systems reveal that some gonococci survive and replicate within PMNs and suggest that gonococci defend themselves against PMNs in two ways: they express virulence factors that defend against PMNs’ oxidative and non-oxidative antimicrobial components, and they modulate the ability of PMNs to phagocytose gonococci and to release antimicrobial components. In this review, we will highlight the varied and complementary approaches used by N. gonorrhoeae to resist clearance by human PMNs, with an emphasis on gonococcal gene products that modulate bacterial-PMN interactions. Understanding how some gonococci survive exposure to PMNs will help guide future initiatives for combating gonorrheal disease.

/pdf/resistance-of-neisseria-gonorrhoeae-to-neutrophils-37hujc9e8b.pdf

Resistance of Neisseria Gonorrhoeae to Neutrophils

O2 consumption induced by combining gonococci (GC) and neutrophils (PMN) was much higher than the sum of the two components’ individuals rates, suggesting PMN stimulated GC O2 uptake. The effect was independent of GC piliation, colony opacity, or serum resistance. The promyelocytic HL-60 cell line (which cannot undergo a “respiratory burst”) induced a 2–3 fold increase in GC O2 consumption, independent of GC phenotype. This appears secondary to a low molecular weight factor(s) released by the cells which may be similar to that previously described in human serum.

Exposure to myeloid and other mammalian cells increases Neisseria gonorrhoeae O2 utilization. Implications for pathogenesis

O2 consumption resulting from interaction of Neisseria gonorrhoeae and human neutrophils represents a composite of O2 consumed by the two cell systems. Experiments studying the relative contribution of each system suggested the possibility that gonococci increased their metabolic activity in response to interaction with neutrophils. This hypothesis was confirmed by demonstrating that undifferentiated HL-60 cells, which are unable to undergo a respiratory burst, induce a two- to three-fold increase in gonococcal O2 consumption. Gonococcal capacity to adhere to HL-60 cells did not correlate with extent of metabolic stimulation. Stimulatory activity was demonstrable in cell-free supernatant from neutrophils or HL-60 cells, and increased with duration of incubation. Supernatant applied to a G-15 Sephadex column yielded fractions that stimulated gonococcal O2 consumption. Elution profiles were similar for HL-60 cells, neutrophils, and a stimulatory factor previously isolated from pooled human serum. This stimulatory factor(s) failed to adhere to DEAE or C-18 HPLC columns. Stimulatory activity release from myeloid cells was inhibited by incubation at 4 degrees C or in the presence of NaF, indicating a critical role for glucose metabolism. Lactate, the principal product of resting neutrophil glucose catabolism, was demonstrable in cell-free supernatants after incubation at 37 degrees C. Lactate accumulation was inhibited by NaF and decreased temperature of incubation. Lactate at levels present in cell-free supernatant increased gonococcal O2 consumption twofold and restored stimulatory activity to dialyzed serum. Live, but not heat-killed gonococci eliminated lactate released from neutrophils during phagocytosis. Gonococci are able to utilize host-derived lactate to enhance their rate of O2 metabolism.

/pdf/phagocyte-derived-lactate-stimulates-oxygen-consumption-by-5onfmob3hw.pdf

Phagocyte-derived lactate stimulates oxygen consumption by Neisseria gonorrhoeae. An unrecognized aspect of the oxygen metabolism of phagocytosis.

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Exposure to myeloid and other mammalian cells increases Neisseria gonorrhoeae O2 utilization. Implications for pathogenesis

Phagocyte-derived lactate stimulates oxygen consumption by Neisseria gonorrhoeae. An unrecognized aspect of the oxygen metabolism of phagocytosis.