leptin and Pneumonia--Pneumococcal

Pneumococcal pneumonia is the leading cause of community-acquired pneumonia. Obesity is a risk factor for pneumonia. Host factors play a critical role in susceptibility to pulmonary pathogens and outcome from pulmonary infections. Obesity impairs innate and adaptive immune responses, important in the host defence against pneumococcal disease. One area of emerging interest in understanding the complex relationship between obesity and pulmonary infections is the role of the hormone leptin. There is a substantive evidence base supporting the associations between obesity, leptin, pulmonary infections and host defence mechanisms. Despite this, there is a paucity of research that specifically focuses on

Topics: Animals; Community-Acquired Infections; Humans; Leptin; Lung; Mice; Obesity; Pneumonia, Pneumococcal; Streptococcus pneumoniae

The adipocyte-derived hormone leptin is an important regulator of appetite and energy expenditure and is now appreciated for its ability to control innate and adaptive immune responses. We have reported previously that the leptin-deficient ob/ob mouse exhibited increased susceptibility to the Gram-negative bacterium Klebsiella pneumoniae. In this report we assessed the impact of chronic leptin deficiency, using ob/ob mice, on pneumococcal pneumonia and examined whether restoring circulating leptin to physiological levels in vivo could improve host defences against this pathogen. We observed that ob/ob mice, compared with wild-type (WT) animals, exhibited enhanced lethality and reduced pulmonary bacterial clearance following Streptococcus pneumoniae challenge. These impairments in host defence in ob/ob mice were associated with elevated levels of lung tumour necrosis factor (TNF)-alpha, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E(2) (PGE(2)), lung neutrophil polymorphonuclear leukocyte (PMN) counts, defective alveolar macrophage (AM) phagocytosis and PMN killing of S. pneumoniae in vitro. Exogenous leptin administration to ob/ob mice in vivo improved survival and greatly improved pulmonary bacterial clearance, reduced bacteraemia, reconstituted AM phagocytosis and PMN H(2)O(2) production and killing of S. pneumoniae in vitro. Our results demonstrate, for the first time, that leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Further investigations are warranted to determine whether there is a potential therapeutic role for this adipokine in immunocompromised patients.

Topics: Animals; Bacteremia; Cytokines; Disease Susceptibility; Drug Evaluation, Preclinical; Female; Hydrogen Peroxide; Leptin; Leukocyte Count; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Neutrophil Infiltration; Phagocytosis; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Survival Analysis

Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia.. To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice.. C57BL/6 mice were either fed ad libitum or fasted for 48 h and given an intraperitoneal injection of saline or recombinant leptin (1 microg/g of body weight) twice daily for 48 h before bacterial challenge. Mice were challenged with 10(5) cfu of Streptococcus pneumoniae via the intranasal route.. Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts and interleukin-6 and macrophage inflammatory protein-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium-ionophore-stimulated leukotriene B(4) synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, alveolar macrophage bacterial killing, and leukotriene B(4) synthesis.. These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically.

Topics: Acute Disease; Animals; Blood Glucose; Body Weight; Bronchoalveolar Lavage; Corticosterone; Disease Models, Animal; Fasting; Interleukin-6; Leptin; Leukocytes; Leukotriene B4; Lung; Mice; Mice, Inbred C57BL; Neutrophils; Phagocytosis; Pneumonia, Pneumococcal; Sodium Chloride; Starvation; Streptococcus pneumoniae

Topics: Animals; Critical Illness; Humans; Immunity; Leptin; Lung; Malnutrition; Mice; Pneumonia, Pneumococcal; Streptococcus pneumoniae

Leptin is a pleiotrophic protein mainly produced by adipocytes that has been implicated as a link between nutritional status and immune function. Severe bacterial infection is associated with elevated plasma levels of leptin. To determine the role of leptin in the host response to bacterial pneumonia leptin deficient ob/ob mice and normal wild-type (WT) mice were intranasally infected with different doses of the Gram-positive pathogen Streptococcus (S.) pneumoniae or the Gram-negative bacterium Klebsiella (K.) pneumoniae. After infection with lower doses of either pathogen ob/ob mice displayed lower pulmonary levels of proinflammatory cytokines, in particular tumor necrosis factor-alpha and chemokines. However, after infection with a higher dose of S. pneumoniae or K. pneumoniae the lung concentrations of these inflammatory mediators did not differ between ob/ob and WT mice. In addition, the extent and severity of lung inflammation, as assessed by semi-quantitative histopathology scores, were similar in both mouse strains. Finally, leptin deficiency did not impact on the bacterial outgrowth in the lungs during either Gram-positive or Gram-negative pneumonia irrespective of the infective dose. These data suggest that although leptin may play a modest role in the regulation of inflammation during bacterial pneumonia, it does not contribute to host defense mechanisms that act to limit the outgrowth of S. pneumoniae or K. pneumoniae in the lower airways.

Topics: Animals; Immunity; Inflammation; Klebsiella Infections; Klebsiella pneumoniae; Leptin; Male; Mice; Mice, Inbred C57BL; Pneumonia, Pneumococcal