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Mucosa-associated Escherichia coli are increased in Crohn's disease (CD) and colorectal cancer (CRC). CD isolates replicate within macrophages but the specificity of this effect for CD and its mechanism are unclear. Gentamicin exclusion assay was used to assess E. coli replication within J774.A1 murine macrophages. E. coli growth was assessed following acid, low-nutrient, nitrosative, oxidative and superoxide stress, mimicking the phagolysosome. Twelve of 16 CD E. coli isolates replicated >2-fold within J774.A1 macrophages; likewise for isolates from 6/7 urinary tract infection (UTI), 8/9 from healthy subjects, compared with 2/6 ulcerative colitis, 2/7 colorectal cancer and 0/3 laboratory strains. CD mucosal E. coli were tolerant of acidic, low-nutrient, nitrosative and oxidative stress. Replication within macrophages correlated strongly with tolerance to superoxide stress (rho = 0.44, p = 0.0009). Exemplar CD E. coli HM605 and LF82 were unable to survive within Nfκb1-/- murine bone marrow-derived macrophages. In keeping with this, pre-incubation of macrophages with hydrocortisone (0.6 µM for 24 h) caused 70.49 ± 12.11% inhibition of intra-macrophage replication. Thus, CD mucosal E. coli commonly replicate inside macrophages, but so do some UTI and healthy subject strains. Replication correlates with resistance to superoxide and is highly dependent on macrophage NF-κB signalling. This may therefore be a good therapeutic target.
Pubmed ID: 31181736
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Recently, our team completed an NINDS-funded, Phase IIa double-blinded, placebo-controlled pilot clinical trial that examined the pharmacokinetics, safety, and activity of progesterone, a steroid found to have powerful neuroprotective effects in multiple animal models of brain injury. Our pilot study demonstrated a 50% reduction in death among severe TBI patients and less disability among moderate TBI patients treated with progesterone. Based on these promising results and supportive preclinical data, we are conducting a large, phase III clinical trial (ProTECT III) to definitively assess the safety and efficacy of this treatment for adults with moderate to severe acute TBI. The study is slated to begin August 2008. WHY Progesterone: Although progresterone is widely considered a sex steroid, it is also a potent neurosteroid. Progesterone is naturally synthesized in the CNS. A large and growing body of animal studies indicate that early administration of progesterone after TBI reduces cerebral edema, neuronal loss, and behavioral deficits in laboratory animals. Certain properties of progesterone make it an ideal therapeutic candidate. First, in contrast to most drugs tested to date, progesterone rapidly enters the brain and reaches equilibrium with the plasma within an hour of administration. Second, unlike other experimental agents, progesterone has a long history of safe use in humans. Finally, the findings of our pilot clinical trial (presented in the Preliminary Data Section, below) indicate that progesterone has consistent and predictable pharmacokinetic properties, is unlikely to produce harm, and may be efficacious for treating acute TBI in humans.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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