The prototypical neutrophil recruitment cascade is a multistep process requiring the endothelium to express molecules (selectins) to slow circulating leukocytes (tethering), followed by vascular rolling and firm adhesion (selectins and integrins)( 31).
FACEBOOK JOHN KUBES CALIFORNIA FREE
Both humans and mice do not have pulmonary intravascular macrophages 21, 22, however pathogens can sequester within the massive surface area of the capillary network potentially evading removal ( 26) therefore, it is unclear how the host detects and removes bloodstream pathogens within this macrophage free vascular labyrinth. As well, the best prognostic factor in bacteremic cancer patients is the recovery of neutrophil counts ( 30). Despite the clear role of resident macrophages in clearing blood borne pathogens, the major risk factor for acquiring a bloodstream infection is not macrophage dysfunction but neutropenia ( 29).
/cdn.vox-cdn.com/uploads/chorus_image/image/46844844/CK9ZW4NVEAAcVfK.0.0.jpg "facebook john kubes california")
The liver is home to resident intravascular macrophages called Kupffer cells, which catch free flowing bacteria via the complement receptor Ig (CRIg) as they filter through the sinusoids ( 26– 28). This resident cellular defense system does not require active pursuit or tracking of the pathogen but absolutely requires that the bug remain in the free flow circulation.
The biological relevance of this rapid non-transcriptional response to host defence in vivo is limited.Ĭonventionally, the capture of free-flowing particles and circulating pathogens is attributed to stationary resident mononuclear cells within the liver and spleen ( 23– 25). Contrary to this classical view, but for the most part ignored, is the observation that LPS can induce increases in neutrophil cell surface adhesion molecules and binding in minutes ( 21, 22). LPS, by contrast, classically requires hours for effector function to be fully elicited through transcription and translation. Each of these effector functions occur in seconds following bacteria stimulation and has been attributed to opsonisation and rapid production of pro-inflammatory complement fragments ( 20). Neutrophils do not require protein synthesis to perform phagocytosis, oxidant production, degranulation or NET release when reacting to pathogens ( 19). Indeed, macrophage begin to synthesize TNF-alpha and numerous chemokines while endothelium begins to synthesize E-selectin, ICAM-1 and VCAM-1 and additional chemokines in an attempt to recruit the main effector cell of innate immunity, namely the neutrophil ( 18). The signalling pathway is extremely well established and includes the activation of Myd88, IRAK-4 leading to NFκB translocation to the nucleus, and subsequent transcription and translation of various pro-inflammatory molecules ( 15– 17). Lipopolysaccharide (LPS) is the major pathogen associated molecular pattern of gram-negative bacteria that binds and stimulates TLR4 ( 14). Likewise, the innate immune system must provide immediate protection when pathogens enter the bloodstream until the administration of effective antibiotics. It is now recognized that sepsis is a medical emergency, similar to heart attacks and strokes, whereby every hour of untreated infection dramatically decreases the likelihood of patient survival ( 13). Alarmingly, gram-negative bacteria are rapidly developing resistance to broad-spectrum antibiotics and in some circumstances have become pan-antibiotic resistant ( 11, 12). Escherichia coli, is a major overall causative organism found in community acquired and hospital acquired bloodstream infections ( 3, 10). Bloodstream infections are common both in the community ( 3– 5) and in the hospital ( 6– 9). Of particular concern is that sepsis with bacteremia, or bloodstream infection, has even worse outcomes in humans ( 2). Sepsis is a deleterious host response to an infection that continues to have an unacceptably high mortality( 1).
0 kommentar(er)
