Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine ...model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses.
An increasing number of older people receive organ transplants for various end-stage conditions. Although organ transplantation is an effective therapy for older patients (i.e., older than 65 years ...of age), such as in end-stage renal disease, this therapy has not been optimized for older patients because of our lack of understanding of the effect of aging and the immune response to organ transplantation. Here, we provide an overview of the impact of aging on both the allograft and the recipient and its effect on the immune response to organ transplantation. We describe what has been determined to date, discuss existing gaps in our knowledge, and make suggestions on necessary future studies to optimize organ transplantation for older people.
Neutrophils clear viruses, but excessive neutrophil responses induce tissue injury and worsen disease. Aging increases mortality to influenza infection; however, whether this is due to impaired viral ...clearance or a pathological host immune response is unknown. Here we show that aged mice have higher levels of lung neutrophils than younger mice after influenza viral infection. Depleting neutrophils after, but not before, infection substantially improves the survival of aged mice without altering viral clearance. Aged alveolar epithelial cells (AECs) have a higher frequency of senescence and secrete higher levels of the neutrophil-attracting chemokines CXCL1 and CXCL2 during influenza infection. These chemokines are required for age-enhanced neutrophil chemotaxis in vitro. Our work suggests that aging increases mortality from influenza in part because senescent AECs secrete more chemokines, leading to excessive neutrophil recruitment. Therapies that mitigate this pathological immune response in the elderly might improve outcomes of influenza and other respiratory infections.
The elderly exhibit increased mortality to influenza viral infection for unclear reasons. Mice are frequently used to model how aging impacts disease. Several studies have shown that aged mice ...exhibit an increased mortality to influenza virus, but two recent studies demonstrated the opposite. These two studies administered the virus intranasally in 20 µL, whereas the other studies used a viral inoculum in at least 30 µL. To determine whether the volume of the inoculum could explain the conflicting reports, we infected young and aged mice via intranasal instillation of 40 µL or 20 µL containing 1 x 104 plaque‐forming units (PFU) of H1N1 influenza virus. We found that intranasal administration of 40 µL but not 20 µL of inoculum resulted in age‐dependent mortality in mice. Compared to aged mice infected with 40 µL inoculum, those infected with 20 µL inoculum showed reduced levels of live virus and IFN‐β in the lung 3 days postinfection. Furthermore, aged mice administered 40 µL of Evans blue intranasally displayed increased dye retention in their bronchoalveolar lavage fluid compared to those administered 20 µL of Evans blue. Our data demonstrate that the inoculating volume of virus is critical for adequate delivery of influenza virus to the lung and thus for efficient infection of aged mice. These findings shed light on discrepant results in the literature regarding aged mice and influenza infection, and establish that mice can be used to examine how aging impacts the response to this biomedically important infection.
Current biofuel feedstock crops such as corn lead to large environmental losses of N through nitrate leaching and N2O emissions; second‐generation cellulosic crops have the potential to reduce these ...N losses. We measured N losses and cycling in establishing miscanthus (Miscanthus × giganteus), switchgrass (Panicum virgatum L. fertilized with 56 kg N ha−1 yr−1), and mixed prairie, along with a corn (Zea mays L.)–corn–soybean Glycine max (L.) Merr. rotation (corn fertilized at 168–202 kg N ha−1). Nitrous oxide emissions, soil N mineralization, mid‐profile nitrate leaching, and tile flow and nitrate concentrations were measured. Perennial crops quickly reduced nitrate leaching at a 50‐cm soil depth as well as concentrations and loads from the tile systems (year 1 tile nitrate concentrations of 10–15 mg N L−1 declined significantly by year 4 in all perennial crops to <0.6 mg N L−1, with losses of <0.8 kg N ha−1 yr−1). Nitrous oxide emissions were 2.2 to 7.7 kg N ha−1 yr−1 in the corn–corn–soybean rotation but were <1.0 kg N ha−1 yr−1 by year 4 in the perennial crops. Overall N balances (atmospheric deposition + fertilization + soybean N2 fixation – harvest, leaching losses, and N2O emissions) were positive for corn and soybean (22 kg N ha−1 yr−1) as well as switchgrass (9.7 kg N ha−1 yr−1) but were −18 and −29 kg N ha−1 yr−1 for prairie and miscanthus, respectively. Our results demonstrate rapid tightening of the N cycle as perennial biofuel crops established on a rich Mollisol soil.
Many studies have reported associations between air pollution particles with an aerodynamic diameter <2.5 μm (fine particulate matter (PM)) and adverse cardiovascular effects. However, there is an ...increased concern that so-called ultrafine PM which comprises the smallest fraction of fine PM (aerodynamic diameter <0.1 μm) may be disproportionately toxic relative to the 0.1-2.5 μm fraction. Ultrafine PM is not routinely measured in state monitoring networks and is not homogenously dispersed throughout an airshed but rather located in hot spots such as near combustion sources (e.g., roads), making it difficult for epidemiology studies to associate exposure to ultrafine PM with adverse health effects. Thirty four middle-aged individuals with metabolic syndrome were exposed for 2 h while at rest in a randomized crossover design to clean air and concentrated ambient ultrafine particles (UCAPS) for 2 h. To further define potential risk, study individuals carrying the null allele for GSTM1 (a prominent antioxidant gene) were identified by genotyping. Blood was obtained immediately prior to exposure, and at 1 and 20 h afterward. Continuous Holter monitoring began immediately prior to exposure and continued for 24 h. Based on changes we observed in previous CAPS studies, we hypothesized that ultrafine CAPS would cause changes in markers of blood inflammation and fibrinolysis as well as changes in heart rate variability and cardiac repolarization. GSTM1 null individuals had altered cardiac repolarization as seen by a change in QRS complexity following exposure to UCAPS and both the entire study population as well as GSTM1 null individuals had increased QT duration. Blood plasminogen and thrombomodulin were decreased in the whole population following UCAPS exposure, whereas C-reactive protein (CRP) and SAA were increased. This controlled human exposure study is the first to show that ambient ultrafine particles can cause cardiovascular changes in people with metabolic syndrome, which affects nearly a quarter of the U.S. adult population.
Aims
Tildrakizumab, an interleukin (IL)‐23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, ...cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL‐23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease–drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis.
Methods
This was an open‐label, fixed‐sequence, two‐period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg 3A4, caffeine 200 mg 1A2, warfarin 10 mg 2C9, omeprazole 40 mg 2C19 and dextromethorphan 30 mg 2D6), followed by a 7‐day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin‐6 (IL‐6) and high‐sensitivity C‐reactive protein (hs‐CRP), were assessed.
Results
Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL‐6 or hs‐CRP. Treatment with tildrakizumab was generally well tolerated.
Conclusion
In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug–drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti‐inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.
We evaluated the biogeochemical cycling and relative greenhouse gas (GHG) mitigation potential of proposed biofuel feedstock crops by modeling growth dynamics of Miscanthus × giganteus Greef et ...Deuter (miscanthus), Panicum virgatum L. (switchgrass), Zea mays L. (corn), and a mixed prairie community under identical field conditions. DAYCENT model simulations for miscanthus were parameterized with data from trial plots in Europe and Illinois, USA. Switchgrass, corn, and prairie ecosystems were simulated using parameters published in the literature. A previously unknown source of nitrogen (N) was necessary to balance the plant nutrient budget in miscanthus crops, leading us to hypothesize that miscanthus growth depends on N-fixation. We tested for nitrogenase activity by acetylene reduction of whole rhizomes and bacteria isolated from the rhizosphere and miscanthus tissue. Our results supported the hypothesis that biological N-fixation contributed to the N demand of miscanthus, a highly productive perennial grass. Corn agro-ecosystems emit 956 to 1899 g CO₂eq m⁻²y⁻¹ greater GHGs (including CO₂, N₂O, CH₄) to the atmosphere than the other biofuel crop alternatives because of greater N₂O emissions from fertilizer additions. Of the feedstock crops evaluated in this study, miscanthus would result in the greatest GHG reduction.
Diesel exhaust particles and airway inflammation Ghio, Andrew J; Smith, Candice B; Madden, Michael C
Current opinion in pulmonary medicine,
2012-March, 2012-Mar, 2012-03-00, 20120301, Letnik:
18, Številka:
2
Journal Article
Odprti dostop
PURPOSE OF REVIEWEpidemiologic investigation has associated traffic-related air pollution with adverse human health outcomes. The capacity of diesel exhaust particles (DEPs), a major emission source ...air pollution particle, to initiate an airway inflammation has subsequently been investigated. We review the recent controlled human exposures to diesel exhaust and DEPs, and summarize the investigations into the associations between this emission source air pollution particle and airway inflammation.
RECENT FINDINGSUsing bronchoalveolar lavage, bronchial biopsies, and sputum collection, studies have demonstrated inflammation in the airways of healthy individuals after exposure to diesel exhaust and DEPs. This inflammation has included neutrophils, eosinophils, mast cells, and lymphocytes. Elevated expression and concentrations of inflammatory mediators have similarly been observed in the respiratory tract after diesel exhaust and DEP exposure. An increased sensitivity of asthmatic individuals to the proinflammatory effects of DEPs has not been confirmed.
SUMMARYInflammation after diesel exhaust and DEP exposure is evident at higher concentrations only; there appears to be a threshold dose for DEPs approximating 300 μg/m. The lack of a biological response to DEPs at lower concentrations may reflect a contribution of gaseous constituents or interactions between DEPs and gaseous air pollutants to the human inflammatory response and function loss.
The emergence of resistance to multiple antimicrobial agents by pathogenic bacteria has become a significant global public health threat. Multi-drug-resistant (MDR) Gram-negative bacteria have become ...particularly problematic, as no new classes of small-molecule antibiotics for Gram-negative bacteria have emerged in over two decades. We have developed a combinatorial screening process for identifying mixed ligand monolayer/gold nanoparticle conjugates (2.4 nm diameter) with antibiotic activity. The method previously led to the discovery of several conjugates with potent activity against the Gram-negative bacterium Escherichia coli. Here we show that these conjugates are also active against MDR E. coli and MDR Klebsiella pneumoniae. Moreover, we have shown that resistance to these nanoparticles develops significantly more slowly than to a commercial small-molecule drug. These results, combined with their relatively low toxicity to mammalian cells and biocompatibility in vivo, suggest that gold nanoparticles may be viable new candidates for the treatment of MDR Gram-negative bacterial infections.
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