Impaired leukotriene C4 generation in granulocytes from protein‐energy malnourished chronically ill elderly

Cederholm, Tommy; Lindgren, Jan; Palmblad, Jan

doi:10.1046/j.1365-2796.2000.00691.x

Cited by 25 publications

(23 citation statements)

References 43 publications

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“…The link between leptin and leukotriene synthesis is also novel, and the mechanism responsible for this observation remains to be explored. Interestingly, others have demonstrated impaired leukotriene synthesis in malnutrition (38,39). We did not find differences between the WT and leptin-deficient mice in lung homogenate TNF-␣, IL-12, and MIP-2.…”

Section: Discussioncontrasting

confidence: 50%

“…These results indicate that leptin is an essential component of pulmonary antibacterial host defense in mice, and suggest that leukotrienes are important mediators of the leptin effect. While an important role for leptin in human pulmonary host defense has not been established, it is noteworthy that individuals who are most susceptible to bacterial pneumonia (the elderly, the HIV infected, the malnourished, and diabetics) exhibit altered leptin secretion or responsiveness as well as reduced leukotriene synthesis (38,39,52,53).…”

Section: Discussionmentioning

confidence: 99%

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Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia

Mancuso

Gottschalk

Phare

et al. 2002

The Journal of Immunology

313

266

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Leptin is an adipocyte-derived hormone that is secreted in correlation with total body lipid stores. Serum leptin levels are lowered by the loss of body fat mass that would accompany starvation and malnutrition. Recently, leptin has been shown to modulate innate immune responses such as macrophage phagocytosis and cytokine synthesis in vitro. To determine whether leptin plays a role in the innate host response against Gram-negative pneumonia in vivo, we compared the responses of leptin-deficient and wild-type mice following an intratracheal challenge of Klebsiella pneumoniae. Following K. pneumoniae administration, we observed increased leptin levels in serum, bronchoalveolar lavage fluid, and whole lung homogenates. In a survival study, leptin-deficient mice, as compared with wild-type mice, exhibited increased mortality following K. pneumoniae administration. The increased susceptibility to K. pneumoniae in the leptin-deficient mice was associated with reduced bacterial clearance and defective alveolar macrophage phagocytosis in vitro. The exogenous addition of very high levels of leptin (500 ng/ml) restored the defect in alveolar macrophage phagocytosis of K. pneumoniae in vitro. While there were no differences between wild-type and leptin-deficient mice in lung homogenate cytokines TNF-α, IL-12, or macrophage-inflammatory protein-2 after K. pneumoniae administration, leukotriene synthesis in lung macrophages from leptin-deficient mice was reduced. Leukotriene production was restored by the addition of exogenous leptin (500 ng/ml) to macrophages in vitro. This study demonstrates for the first time that leptin-deficient mice display impaired host defense in bacterial pneumonia that may be due to a defect in alveolar macrophage phagocytosis and leukotriene synthesis.

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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia

Mancuso

Gottschalk

Phare

et al. 2002

The Journal of Immunology

313

266

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“…For (5,6,9,10,16). Data from each of these genotypes could predict that both of the parallel categories of patients would demonstrate an improved ability to clear pulmonary bacterial pathogens after the exogenous administration of LTB 4 .…”

Section: Discussionmentioning

confidence: 99%

Intrapulmonary Administration of Leukotriene B₄Enhances Pulmonary Host Defense against Pneumococcal Pneumonia

Mancuso¹,

Lewis

Serezani

et al. 2010

Infect Immun

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Leukotriene B 4 (LTB 4 ) is a potent lipid mediator of inflammation formed by the 5-lipoxygenase (5-LO)-catalyzed oxidation of arachidonic acid. We have previously shown that (i) LTB 4 is generated during infection, (ii) its biosynthesis is essential for optimal antimicrobial host defense, (iii) LT deficiency is associated with clinical states of immunocompromise, and (iv) exogenous LTB 4 augments antimicrobial functions in phagocytes. Here, we sought to determine whether the administration of LTB 4 has therapeutic potential in a mouse model of pneumonia. Wild-type and 5-LO knockout mice were challenged with Streptococcus pneumoniae via the intranasal route, and bacterial burdens, leukocyte counts, and cytokine levels were determined. LTB 4 was administered via the intraperitoneal, intravenous, and intranasal routes prior to pneumococcal infection and by aerosol 24 h following infection. Leukocytes recovered from mice given S. pneumoniae and treated with aerosolized LTB 4 were evaluated for expression levels of the p47phox subunit of NADPH oxidase. Intrapulmonary but not systemic pretreatment with LTB 4 significantly reduced the lung S. pneumoniae burden in wild-type mice. Aerosolized LTB 4 was effective at improving lung bacterial clearance when administered postinoculation in animals with established infection and exhibited greater potency in 5-LO knockout animals, which also exhibited greater baseline susceptibility. Augmented bacterial clearance in response to LTB 4 was associated with enhanced monocyte recruitment and leukocyte expression of p47phox. The results of the current study in an animal model serve as a proof of concept for the potential utility of treatment with aerosolized LTB 4 as an immunostimulatory strategy in patients with bacterial pneumonia.

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“…Experimental protein-calorie malnutrition in rats resulted in impaired production of LTB 4 by alveolar macrophages (84). In studies of undernourished hospitalized patients, LT synthesis by granulocytes was decreased as compared with cells from healthy controls (85). It is established that serum leptin levels decline rapidly during periods of caloric insufficiency (86), and it is likely that leptin deficiency during malnutrition is an important cause of defective LT synthesis and its associated immunosuppression.…”

Section: Lt Deficiency In States Of Immunosuppressionmentioning

confidence: 99%

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Peters‐Golden¹,

Canetti²,

Mancuso

et al. 2005

The Journal of Immunology

279

244

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Leukotrienes are bronchoconstrictor and vasoactive lipid mediators that are targets in the treatment of asthma. Although they are increasingly recognized to exert broad proinflammatory effects, their role in innate immune responses is less well appreciated. These molecules are indeed synthesized by resident and recruited leukocytes during infection. Acting via cell surface G protein-coupled receptors and subsequent intracellular signaling events, they enhance leukocyte accumulation, phagocyte capacity for microbial ingestion and killing, and generation of other proinflammatory mediators. Interestingly, a variety of acquired states of immunodeficiency, such as HIV infection and malnutrition, are characterized by a relative deficiency of leukotriene synthesis. The data reviewed herein point to leukotrienes as underappreciated yet highly relevant mediators of innate immunity.

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Impaired leukotriene C4 generation in granulocytes from protein‐energy malnourished chronically ill elderly

Cited by 25 publications

References 43 publications

Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia

Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia

Intrapulmonary Administration of Leukotriene B₄Enhances Pulmonary Host Defense against Pneumococcal Pneumonia

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

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Impaired leukotriene C4 generation in granulocytes from protein‐energy malnourished chronically ill elderly

Cited by 25 publications

References 43 publications

Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia

Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia

Intrapulmonary Administration of Leukotriene B4Enhances Pulmonary Host Defense against Pneumococcal Pneumonia

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

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Intrapulmonary Administration of Leukotriene B₄Enhances Pulmonary Host Defense against Pneumococcal Pneumonia