Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

Quinton, Lee J.; Mizgerd, Joseph P.

doi:10.1146/annurev-physiol-021014-071937

Cited by 95 publications

(121 citation statements)

References 156 publications

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“…Bacterial killing in the lungs relies on innate immunity, including that provided by recruited neutrophils and other extravasated plasma constituents during inflammation (37). In order to determine whether local inflammation was compromised by STAT3 deficiency, we measured BALF neutrophils and total protein concentrations ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3 and 4). We utilized a multiplex bead array to determine the concentrations of 10 cytokines, all of which are relevant to pneumonia and/or lung injury (37,38): IL-1␤, IL-6, IL-10, IL-17, G-CSF, GM-CSF, CXCL1, TNF-␣, LIF, and CXCL2. We observed several patterns of cytokine kinetics in the airspaces, ranging from increases due to E. coli infection to no change at all, but there were no changes in BALF cytokine concentrations due to genotype (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

et al. 2015

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e Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10 6 CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3 ؊/؊ ). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3 ؊/؊ mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3 ؊/؊ mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3 ؊/؊ mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility. Sepsis is a complex immunopathological syndrome defined by the systemic inflammatory response to infection and is a leading contributor to morbidity and mortality in intensive care units as evidenced by approximately 750,000 cases per year (2% of all hospital admissions) (1-3). This multifaceted, systemic inflammatory response can be further complicated by organ dysfunction (severe sepsis) and hypotension (septic shock), all of which lead to a complex, variable syndrome with mortality rates between 30 and 50% (4). While pneumonia is the leading cause of sepsis, with about one-half of all sepsis cases originating as respiratory infections (2), sepsis also greatly increases a patient's subsequent susceptibility to bacterial pneumonia (5). In fact, 10 to 30% of mechanically ventilated, septic shock patients develop ventilator-associated pneumonia (6). This positive association extends beyond ventilator-related circumstances and has been corroborated experimentally by multiple studies demonstrating deleterious effects of sepsis and/or endotoxemia on pneumonia outcomes (7-15). With the rapid increase in prevalence of drugresistant pathogens and the limited treatment options available, there is a growing need to develop novel pharmaceutical interventions...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

et al. 2015

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“…Our results suggest two distinct mechanisms contributing to the impaired defence against Klebsiella in the airways of LysMcre- Hsp90b1 -flox mice: a reduced capacity of alveolar macrophages to respond to this bacterium by releasing pro-inflammatory cytokines, and a diminished ability of these cells to phagocytose Klebsiella. The reduced lung levels of TNF-α and IL-1β in LysMcre- Hsp90b1 -flox mice may jeopardize an adequate innate immune response by providing a less potent chemotactic gradient for neutrophil influx to the site of infection [26–29], an important defensive mechanism in pneumonia [30]. In particular, adequate TNF-α release early after invasion of Klebsiella of the lower airways has been shown of utmost importance for protective immunity [31,32].…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum chaperone gp96 in macrophages is essential for protective immunity during Gram‐negative pneumonia

Anas

Vos

Hoogendijk

et al. 2015

The Journal of Pathology

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Klebsiella pneumoniae is among the most common gram-negative bacteria that cause pneumonia. Gp96 is an endoplasmic reticulum chaperone that is essential for the trafficking and function of Toll-like receptors (TLRs) and integrins. To determine the role of gp96 in myeloid cells in host defence during Klebsiella pneumonia. Mice homozygous for the conditional Hsp90b1 allele encoding gp96 were crossed with mice expressing Cre-recombinase under control of the LysM promoter to generate LysMcre-Hsp90b1-flox mice. LysMcre-Hsp90b1-flox mice showed absence of gp96 protein in macrophages and partial depletion in monocytes and granulocytes. This was accompanied by almost complete absence of TLR2 and TLR4 on macrophages. Likewise, integrin subunits CD11b and CD18 were not detectable on macrophages, while being only slightly reduced on monocytes and granulocytes. Gp96-deficient macrophages did not release pro-inflammatory cytokines in response to Klebsiella and displayed reduced phagocytic capacity independent of CD18. LysMcre-Hsp90b1-flox mice were highly vulnerable to lower airway infection induced by K. pneumoniae, as reflected by an enhanced bacterial growth and a higher mortality rate. The early inflammatory response in Hsp90b1-flox mice was characterized by a strongly impaired recruitment of granulocytes into the lungs, accompanied by an attenuated production of proinflammatory cytokines, while the inflammatory response during late stage pneumonia was not dependent on the presence of gp96. Blocking CD18 did not reproduce the impaired host defence of LysMcre-Hsp90b1-flox mice during Klebsiella pneumonia. These data indicate that macrophage gp96 is essential for protective immunity during gram-negative pneumonia by regulating TLR expression.

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“…IAV, influenza A virus infection. susceptibility to superinfections, please refer to recently published review articles (56,57).…”

Section: Influenza-induced Changes To the Lung Environment And Suscepmentioning

confidence: 99%

Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

2015

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cSeasonal influenza virus infection presents a major strain on the health care system. Influenza virus infection has pandemic potential, which was repeatedly observed during the last century. Severe disease may occur in the young, in the elderly, in those with preexisting lung disease, and in previously healthy individuals. A common cause of severe influenza pathogenesis is superinfection with bacterial pathogens, namely, Staphylococcus aureus and Streptococcus pneumoniae. A great deal of recent research has focused on the immune pathways involved in influenza-induced susceptibility to secondary bacterial pneumonia. Both innate and adaptive antibacterial host defenses are impaired in the context of preceding influenza virus infection. The goal of this minireview is to highlight these findings and synthesize these data into a shared central theme of pathogenesis.

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Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

Cited by 95 publications

References 156 publications

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

Endoplasmic reticulum chaperone gp96 in macrophages is essential for protective immunity during Gram‐negative pneumonia

Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

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