The α-Tocopherol Form of Vitamin E Reverses Age-Associated Susceptibility to Streptococcus pneumoniae Lung Infection by Modulating Pulmonary Neutrophil Recruitment

Abstract

Streptococcus pneumoniae infections are an important cause of morbidity and mortality in older patients. Uncontrolled neutrophil-driven pulmonary inflammation exacerbates this disease. To test whether the α-tocopherol (α-Toc) form of vitamin E, a regulator of immunity, can modulate neutrophil responses as a preventive strategy to mitigate the age-associated decline in resistance to S. pneumoniae, young (4 mo) and old (22–24 mo) C57BL/6 mice were fed a diet containing 30-PPM (control) or 500-PPM (supplemented) α-Toc for 4 wk and intratracheally infected with S. pneumoniae. Aged mice fed a control diet were exquisitely more susceptible to S. pneumoniae than young mice. At 2 d postinfection, aged mice suffered 1000-fold higher pulmonary bacterial burden, 2.2-fold higher levels of neutrophil recruitment to the lung, and a 2.25-fold higher rate of lethal septicemia. Strikingly, α-Toc supplementation of aged mice resulted in a 1000-fold lower bacterial lung burden and full control of infection. This α-Toc–induced resistance to pneumococcal challenge was associated with a 2-fold fewer pulmonary neutrophils, a level comparable to S. pneumoniae–challenged, conventionally fed young mice. α-Toc directly inhibited neutrophil egress across epithelial cell monolayers in vitro in response to pneumococci or hepoxilin-A3, an eicosanoid required for pneumococcus-elicited neutrophil trans-epithelial migration. α-Toc altered expression of multiple epithelial and neutrophil adhesion molecules involved in migration, including CD55, CD47, CD18/CD11b, and ICAM-1. These findings suggest that α-Toc enhances resistance of aged mice to bacterial pneumonia by modulating the innate immune response, a finding that has potential clinical significance in combating infection in aged individuals through nutritional intervention.

Nasopharyngeal Exposure to Streptococcus pneumoniae Induces Extended Age-Dependent Protection against Pulmonary Infection Mediated by Antibodies and CD138+ Cells

“…The elderly are at increased risk of life-threatening invasive pneumococcal infections, and previous work has demonstrated age-associated susceptibility to S. pneumoniae infection in mice (17, 60). Although aged (20- to 22-mo-old) mice were able to survive NP exposure similarly to young controls and generated comparable levels of antipneumococcal Abs, they did not acquire significant postcolonization protection against pulmonary challenge.…”

“…inoculation (2 wk after rifampicin treatment), mice were lightly anesthetized with isoflurane and 50 μl of bacteria was instilled directly to the trachea with the tongue pulled out to facilitate delivery of bacteria directly into the lungs as previously described (17). Mice were monitored closely after intratracheal (i.t.)…”

“…However, T cell–independent Ab responses, such as those elicited by the nonconjugated pneumococcal polysaccharide (PPS) vaccine Pneumovax, can also lead to long-term protection (9, 14). Aging leads to defects in both T cell–dependent and T cell–independent Ab production (15, 16), limiting the efficacy of the current vaccines (15, 17) and contributing to the susceptibility of the elderly to invasive pneumococcal infection.…”

Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection

“…Although PMN recruitment to the site of pathogenic insult is an integral part of innate immune defense, prolonged and robust PMN recruitment can contribute to disease and mortality (7)(8)(9)(10).…”

α-Tocopherol transfer protein mediates protective hypercapnia in murine ventilator-induced lung injury

“…However, important gaps exist in our understanding of the protective effects of α-tocopherol: supplementation protects against lung injury in murine bacterial pneumonia ( Streptococcus pneumoniae ), reducing mortality, bacterial load, and neutrophil transepithelial migration 28. In addition, while α-tocopherol protects against hyperoxic lung injury through antioxidant mechanisms,29 the mechanisms of protection in other lung injury (eg, sepsis) is unclear.…”