Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

Marriott, Helen M.; Jackson, Laura E.; Wilkinson, Thomas S.; Simpson, Alex; Mitchell, Tim; Buttle, David J.; Cross, Simon S.; Ince, Paul G.; Hellewell, Paul G.; Whyte, Moira K. B.; Dockrell, David H.

doi:10.1164/rccm.200707-990oc

Cited by 75 publications

(69 citation statements)

References 50 publications

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“…Intracellular bacterial killing by neutrophils is primarily mediated via the generation of reactive oxygen species (ROS) and reactive nitrogen species (35,42). The importance of the NADPH oxidase to the host defense is shown by the frequent infections resulting from the impaired killing of microbes in patients with chronic granulomatous disease (CGD) (61).…”

Section: R E T R a C T E Dmentioning

confidence: 99%

NOD2 Signaling Contributes to Host Defense in the Lungs against Escherichia coli Infection

Theivanthiran¹,

Batra²,

Balamayooran³

et al. 2012

Infect Immun

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Bacterial pneumonia remains a significant cause of mortality in the United States. The innate immune response is the first line of defense against invading bacteria. Neutrophil recruitment to the lungs is the first step in a multistep sequence leading to bacterial clearance. Ligand interaction with pattern-recognizing receptors (PRRs) leads to chemokine production, which drives neutrophils to the site of infection. Although we demonstrated that RIP2 is important for host defense in the lungs against Escherichia coli, the individual roles of NOD1 and NOD2 in pulmonary defense have not been addressed. Here, we explored the role of NOD2 in neutrophil-mediated host defense against an extracellular pathogen, E. coli. We found enhanced bacterial burden and reduced neutrophil and cytokine/chemokine levels in the lungs of NOD2 ؊/؊ mice following E. coli infection. Furthermore, we observed reduced activation of NF-B and mitogen-activated protein kinases (MAPKs) in the lungs of NOD2 ؊/؊ mice upon E. coli challenge. Moreover, NOD2؊/؊ neutrophils show impaired intracellular bacterial killing. Using NOD2/RIP2 ؊/؊ mice, we observed bacterial burden and neutrophil accumulation in the lungs similar to those seen with NOD2 ؊/؊ mice. In addition, bone marrow-derived macrophages obtained from NOD2/RIP2؊/؊ mice demonstrate a reduction in activation of NF-B and MAPKs similar to that seen with NOD2 ؊/؊ mice in response to E. coli. These findings unveil a previously unrecognized role of the NOD2-RIP2 axis for host defense against extracellular Gram-negative bacteria. This pathway may represent a novel target for the treatment of lung infection/inflammation.

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Section: R E T R a C T E Dmentioning

confidence: 99%

NOD2 Signaling Contributes to Host Defense in the Lungs against Escherichia coli Infection

Theivanthiran¹,

Batra²,

Balamayooran³

et al. 2012

Infect Immun

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“…Studies in mice deficient in the p47 phox subunit indicate a role for NOX isoforms, requiring this subunit for enzyme activation in host defense against Pseudomonas pneumonia (103) and M. tuberculosis pneumonia (21); a potential role of NOX-derived ROS in suppressing neutrophilic inflammation also was suggested (21). Similar findings of a putative ''antiinflammatory'' role for p47 phox =NOX2 are reported in mice challenged with intraperitoneal live Escherichia coli to induce sepsis (35), and in murine models of pneumococcal pneumonia (72), influenza pneumonia (109), and disseminated Cryptococcus neoformans infection (110).…”

Section: Nox Enzymes In Pulmonary Infectious Diseasementioning

confidence: 75%

NOX Enzymes and Pulmonary Disease

Griffith

Pendyala²,

Hecker³

et al. 2009

Antioxidants & Redox Signaling

133

112

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The primary function of the lung is to facilitate the transfer of molecular oxygen (O 2 ; dioxygen) from the atmosphere to the systemic circulation. In addition to its essential role in aerobic metabolism, O 2 serves as the physiologic terminal acceptor of electron transfer catalyzed by the NADPH oxidase (NOX) family of oxidoreductases. The evolution of the lungs and circulatory systems in vertebrates was accompanied by increasing diversification of NOX family enzymes, suggesting adaptive roles for NOX-derived reactive oxygen species in normal physiology. However, this adaptation may paradoxically carry detrimental consequences in the setting of overwhelming=persistent environmental stressors, both infectious and noninfectious, and during the process of aging. Here, we review current understanding of NOX enzymes in normal lung physiology and their pathophysiologic roles in a number of pulmonary diseases, including lung infections, acute lung injury, pulmonary arterial hypertension, obstructive lung disorders, fibrotic lung disease, and lung cancer. Antioxid. Redox Signal. 11, 2505-2516.

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“…Although oxidative stress plays a key role in elimination of intracellular bacteria as well as extracellular bacteria, such as Staphylococcus aureus (5,17,25), our results show that it is not necessary for alveolar macrophage-mediated bacterial clearance. In fact, iNOS Ϫ/Ϫ and gp91 Ϫ/Ϫ mice have been found to be more resistant to pneumococcal infection in terms of host survival (14,18).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Murine Genetic Predisposition to Pneumococcal Infection Reveals a Critical Role of Alveolar Macrophages in Maintaining the Sterility of the Lower Respiratory Tract

2011

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The study of pathogenic mechanisms of disease can be greatly facilitated by studying genetic differences in susceptibility to infection. In the present study, we compared the severity of pneumococcal infection in C57BL/6 (B6) and 129Sv mice. The results showed that 129Sv mice were remarkably more susceptible to pneumococcal infection than B6 mice. Bacterial clearance, proinflammatory mediators, leukocyte recruitment, and phagocyte activities were measured to examine potential immune factors associated with differences in susceptibility to pneumococcal infection. The greater susceptibility of 129Sv mice was associated only with inadequate alveolar macrophage bacterial killing, as indicated by significantly decreased initial bacterial clearance from the respiratory tract. Effective pneumococcal clearance was not dependent upon Toll-like receptor 2 (TLR2) expression, oxidative stress, or matrix metallopeptidase 12 (MMP-12) expression. Furthermore, phagocytosis analysis suggested that the deficiency found in 129Sv alveolar macrophages was not due to a lack of bacterial recognition but, rather, to reduced bacterial uptake. In conclusion, our findings indicate a crucial role of alveolar macrophage phagocytosis during innate defense against pneumococcal infection, which may explain the association of host genetic risk factors with predisposition to pneumococcal infection.There are over 90 Streptococcus pneumoniae serotypes, based on their capsular polysaccharide, and different serotypes vary in the ability to cause disease on the basis of the virulent factors expressed (19,20). On the other hand, host genetic components are also involved in the outcome of pneumococcal infection (2, 4, 22), and host immune status associated with age, respiratory viral infection, chronic diseases, and immunosuppression are all significant risk factors for the development of severe pneumococcal infection (13,16).Although pneumococcus is a major human pathogen, the majority of information about pathogenesis and disease has resulted from mouse studies. It is recognized that there are significant variations in susceptibility to pneumococcal infection among inbred mouse strains (9, 12), and understanding the underlying immune protective mechanisms may explain the association of genetic risk factors with predisposition of the human host to pneumococcal infection.Earlier studies using immunocompetent strains have indicated that mice exhibit a spectrum of resistance to bacterial infection linked to neutrophil recruitment (7, 9, 12). We hypothesized that genetic variation in the capacity of alveolar macrophage-mediated bacterial killing may also exist. Our previous studies have demonstrated a pivotal role of alveolar macrophages in pneumococcal clearance, especially after a sublethal bacterial inoculation (24). However, the overall importance of alveolar macrophages in maintaining the sterility of the lower respiratory tract remains to be firmly established, and the impact of genetic variation on alveolar macrophage function against extracellular...

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Reactive Oxygen Species Regulate Neutrophil Recruitment and Survival in Pneumococcal Pneumonia

Cited by 75 publications

References 50 publications

NOD2 Signaling Contributes to Host Defense in the Lungs against Escherichia coli Infection

NOD2 Signaling Contributes to Host Defense in the Lungs against Escherichia coli Infection

NOX Enzymes and Pulmonary Disease

Analysis of Murine Genetic Predisposition to Pneumococcal Infection Reveals a Critical Role of Alveolar Macrophages in Maintaining the Sterility of the Lower Respiratory Tract

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