Alveolar macrophages maintain lung homeostasis by performing important roles in immunosurveillance and lung surfactant catabolism. They express high levels of CD44 and are one of the few macrophage ...populations that constitutively bind hyaluronan, a ligand for CD44 and component of pericellular and extracellular matrices. Using adoptive transfer experiments and a mouse model of inflammation, we found that alveolar macrophages are initially depleted after an inflammatory insult then rapidly self-renew and return to original numbers after the resolution phase. Monocytes recruited to an inflamed lung differentiate and contribute to the alveolar macrophage pool, but this occurs over a much slower time frame than alveolar macrophage self-renewal. CD44 expression on both fetal and bone marrow-derived alveolar macrophages promoted their survival and provided a competitive advantage over CD44-deficient alveolar macrophages at homeostasis and after inflammation. CD44-mediated hyaluronan binding was induced by the alveolar environment, and this interaction promoted alveolar macrophage survival both ex vivo and in vivo. Without CD44, alveolar macrophages lacked a hyaluronan coat, were more susceptible to death, and were present at lower numbers in the alveolar space. This demonstrates a new role for CD44 and hyaluronan in promoting alveolar macrophage survival.
Hyaluronan is a hygroscopic glycosaminoglycan that contributes to both extracellular and pericellular matrices. While the production of hyaluronan is essential for mammalian development, less is ...known about its interaction and function with immune cells. Here we review what is known about hyaluronan in the lung and how it impacts immune cells, both at homeostasis and during lung inflammation and fibrosis. In the healthy lung, alveolar macrophages provide the first line of defense and play important roles in immunosurveillance and lipid surfactant homeostasis. Alveolar macrophages are surrounded by a coat of hyaluronan that is bound by CD44, a major hyaluronan receptor on immune cells, and this interaction contributes to their survival and the maintenance of normal alveolar macrophage numbers. Alveolar macrophages are conditioned by the alveolar environment to be immunosuppressive, and can phagocytose particulates without alerting an immune response. However, during acute lung infection or injury, an inflammatory immune response is triggered. Hyaluronan levels in the lung are rapidly increased and peak with maximum leukocyte infiltration, suggesting a role for hyaluronan in facilitating leukocyte access to the injury site. Hyaluronan can also be bound by hyaladherins (hyaluronan binding proteins), which create a provisional matrix to facilitate tissue repair. During the subsequent remodeling process hyaluronan concentrations decline and levels return to baseline as homeostasis is restored. In chronic lung diseases, the inflammatory and/or repair phases persist, leading to sustained high levels of hyaluronan, accumulation of associated immune cells and an inability to resolve the inflammatory response.
Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular ...matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44−/− and CD44+/+ OT‐I CD8 T cells were adoptively transferred into mice challenged with Listeria‐OVA, there was a slight increase in the percentage of CD44+/+ cells at the effector site. However, CD44+/+ cells were out‐competed by CD44−/− cells after the contraction phase in the lymphoid tissues, and the CD44−/− cells preferentially formed more memory cells. The hyaluronan‐binding CD44+/+ CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non‐binding CD44+/+ and CD44−/− OT‐I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells toward a terminal effector differentiation state that reduces their ability to form memory cells.
Highly activated CD8 effector T cells bind hyaluronan, an extracellular matrix component, and exhibit increased glycolysis and pAKT compared to activated CD8 T cells that do not bind hyaluronan. The hyaluronan binding cells are preferentially lost during the contraction phase thereby reducing their contribution to the memory pool.
Hyaluronan is made and extruded from cells to form a pericellular or extracellular matrix (ECM) and is present in virtually all tissues in the body. The size and form of hyaluronan present in tissues ...are indicative of a healthy or inflamed tissue, and the interactions of hyaluronan with immune cells can influence their response. Thus, in order to understand how inflammation is regulated, it is necessary to understand these interactions and their consequences. Although there is a large turnover of hyaluronan in our bodies, the large molecular mass form of hyaluronan predominates in healthy tissues. Upon tissue damage and/or infection, the ECM and hyaluronan are broken down and an inflammatory response ensues. As inflammation is resolved, the ECM is restored, and high molecular mass hyaluronan predominates again. Immune cells encounter hyaluronan in the tissues and lymphoid organs and respond differently to high and low molecular mass forms. Immune cells differ in their ability to bind hyaluronan and this can vary with the cell type and their activation state. For example, peritoneal macrophages do not bind soluble hyaluronan but can be induced to bind after exposure to inflammatory stimuli. Likewise, naïve T cells, which typically express low levels of the hyaluronan receptor, CD44, do not bind hyaluronan until they undergo antigen-stimulated T cell proliferation and upregulate CD44. Despite substantial knowledge of where and when immune cells bind hyaluronan, why immune cells bind hyaluronan remains a major outstanding question. Here, we review what is currently known about the interactions of hyaluronan with immune cells in both healthy and inflamed tissues and discuss how hyaluronan binding by immune cells influences the inflammatory response.
Alveolar macrophages (AMs) are CD44 expressing cells that reside in the alveolar space where they maintain lung homeostasis by serving critical roles in immunosurveillance and lipid surfactant ...catabolism. AMs lacking CD44 are unable to bind the glycosaminoglycan, hyaluronan, which compromises their survival and leads to reduced numbers of AMs in the lung. Using RNA sequencing, lipidomics and multiparameter flow cytometry, we demonstrate that CD44
mice have impaired AM lipid homeostasis and increased surfactant lipids in the lung. CD44
AMs had increased expression of CD36, a lipid scavenger receptor, as well as increased intracellular lipid droplets, giving them a foamy appearance. RNA sequencing revealed the differential expression of genes associated with lipid efflux and metabolism in CD44
AMs. Lipidomic analysis showed increased lipids in both the supernatant and cell pellet extracted from the bronchoalveolar lavage of CD44
mice. Phosphatidylcholine species, cholesterol, oxidized phospholipids and levels of reactive oxygen species (ROS) were increased in CD44
AMs. Oxidized phospholipids were more cytotoxic to CD44
AMs and induced greater lung inflammation in CD44
mice. Reconstitution of CD44
mice with CD44
bone marrow as well as adoptive transfer of CD44
AMs into CD44
mice showed that lipid accumulation in CD44
AMs occurred irrespective of the lung environment, suggesting a cell intrinsic defect. Administration of colony stimulating factor 2 (CSF-2), a critical factor in AM development and maintenance, increased AM numbers in CD44
mice and decreased phosphatidylcholine levels in the bronchoalveolar lavage, but was unable to decrease intracellular lipid accumulation in CD44
AMs. Peroxisome proliferator-activated receptor gamma (PPARγ), downstream of CSF-2 signaling and a regulator of lipid metabolism, was reduced in the nucleus of CD44
AMs, and PPARγ inhibition in normal AMs increased their lipid droplets. Thus, CD44 deficiency causes defects in AMs that lead to abnormal lipid accumulation and oxidation, which exacerbates oxidized lipid-induced lung inflammation. Collectively, these findings implicate CD44 as a regulator of lung homeostasis and inflammation.
Objective: To asses the protective effect of phenolic extract of cyperus rotundus rhizomes on biochemical in isoproterenol induced myocardial infraction. Methods: Myocardial infarction was induced in ...rats by intraperitoneally injection of isoproterenol (85mg/kg) for two consecutive days at an interval of 24 h. Rats were treated with phenolic extract of cyperus rotundus rhizomes at two doses (15mg/kg, 30 mg/kg) for period 21 days and isoproterenol was injected on the 21th and 22th day. At the end of experiment i.e. on the 23th day biochemical changes were monitored from control and experimental groups. Results: ISO injected rats showed a significant increase in d-dimer levels. In addition, it also exhibited alteration in the levels of electrolytes (Na+ and Cl−). It also showed significant decrease in level of K+. Pretreatment with phenolic extract of cyperus rotundus rhizomes significantly prevented the ISO induced alteration in biochemical changes. Conclusions: The present result shows that treatment with phenolic extract of cyperus rotundus rhizomes in ISO injected rats significantly attenuates induced myocardial infarction.
The course of the bark beetle-vectored fungus, Leptographium terebrantis S. J. Barras and T. J. Perry, in stemwood growth loss of declining pines in the southeastern United States was assessed in a ...13-year-old loblolly pine (Pinus taeda L.) plantation near Eufaula, Alabama, U.S.A. Using stem inoculation as a surrogate for root infection, we hypothesized that L. terebrantis infection impairs sapwood function and thus limits the tree leaf area (AL), new root production, and stemwood growth. Sterile toothpicks colonized by L. terebrantis at varying inoculum densities was used to elicit host growth responses. In the third year after inoculation, the root pathogen reduced the foliage moisture content, whole-tree leaf area (AL), the ratio of AL to tree sapwood area (AS), and stemwood growth in trees receiving the high inoculation treatment relative to those receiving the low or medium inoculation treatments, or the wound or control treatments after seven months of water deficit. The absence of a similar response to water deficit among trees that were noninoculated, wounded, or inoculated at the low or medium densities suggests that, in the loblolly pine–L. terebrantis pathosystem at our study site, the physiological stress caused by water deficit and the high inoculum density was required for the pathogen to elicit a stemwood growth loss. Thus, in loblolly pine forests of the southeastern United States, where climate and soil conditions yield prolonged periods of physiological stress, the presence of L. terebrantis has the potential to reduce stand volume and widen the gap between the predicted and actual stemwood production.
In recent decades, container stock has become the preferred plant material to regenerate longleaf pine (Pinus palustris Mill.) forests in the southeastern United States. We evaluated the effects of ...container nursery treatments on early and long-term field performance in central Louisiana. Seedlings were grown in four cavity volumes (60–336 mL) with or without copper oxychloride root pruning (Cu or no-Cu) and fertilized at three nitrogen (N) rates. Across treatments, 91% of the seedlings emerged from the grass stage by the second field season, and 88% of the seedlings survived eight years after outplanting (Year 8). Seedlings grown in the largest cavities had greater total heights and stem diameters than those cultured in the 60- and 95-mL cavities through Year 8. Seedlings receiving the least amount of N in the nursery were consistently smaller in stature through Year 8 than seedlings receiving more N. Field growth was unaffected by copper root pruning through Year 8. Foliar mineral nutrient concentrations and seedling nutrient contents of Year 2 seedlings did not respond to nursery treatments. Independent of nursery treatments, seedlings excavated in Year 2 had at least 60% of their first-order lateral roots (FOLRs) originating from the top 4.0 cm of the taproots. The Cu-root-pruned seedlings had twofold the percentage of FOLRs egressed from the top 8.0 cm of the root plug when compared with the no-Cu seedlings. Moreover, the Cu root pruning treatment decreased the percentage of root plug biomass allocated to FOLRs, total within root plug FOLR lengths, and FOLR deformity index. The effects of increasing cavity volume or N rate on the root plug FOLR variables were opposite those of the Cu root pruning treatment. Our results suggest that a tradeoff may exist between seedling stature and a more natural FOLR morphology in outplanted container longleaf pine seedlings.
Background: An association between the phosphodiesterase 4D (PDE4D) gene and risk of ischaemic stroke in an Icelandic population has been suggested by the deCODE group. Methods: A case–control study ...of 151 hospitalised patients with first-ever ischaemic stroke and 164 randomly selected age-matched and sex-matched community controls was conducted. PDE4D genotypes for the six single-nucleotide polymorphisms (SNPs) previously reported to be independently associated with stroke were determined, common haplotypes were inferred using the expectation-maximisation algorithm, and SNP and haplotype associations with stroke were examined. A meta-analysis of published studies examining the association between PDE4D and stroke was also carried out. Results: Our study of Australian patients with stroke showed an independent association between ischaemic stroke and PDE4D SNP 89 (CC: odds ratio (OR) 5.55, 95% confidence interval (CI) 1.02 to 30.19; CA: OR 1.68, 95% CI 0.96 to 2.96; AA: OR 1 (reference)), SNP 87 (CC: OR 2.13, 95% CI 1.08 to 4.20; TC: OR 1.64, 95% CI 0.89 to 3.00; TT: OR 1 (reference)) and SNP 83 (TT: OR 2.16, 95% CI 1.08 to 4.32; TC: OR 1.37, 95% CI 0.77 to 2.43; CC: OR 1 (reference)), and between ischaemic stroke and PDE4D haplotypes at SNP 89–87–83 (A–C–C: OR 2.13, 95% CI 1.15 to 3.96; C–C–T: OR 2.25, 95% CI 1.29 to 3.92), but no association between ischaemic stroke and PDE4D SNP 56, SNP 45 or SNP 41, or with PDE4D haplotypes at SNP 56–45–41. A meta-analysis of nine case–control studies (including our current results) of 3808 stroke cases and 4377 controls confirmed a significant association between stroke and PDE SNP 87 (pooled p = 0.002), SNP 83 (0.003) and SNP 41 (0.003). However, there was statistical heterogeneity (p<0.1) among the studies in the direction of association for each of the individual SNPs tested. Conclusions: Our results and the pooled analyses from all the studies indicate a strong association between PDE4D and ischaemic stroke. This strengthens the evidence that PDE4D plays a key part in the pathogenesis of ischaemic stroke. Heterogeneity among the studies in the direction of association between individual SNPs and stroke suggests that the SNPs tested are in linkage disequilibrium with the causal allele(s).
•Smoked cannabis (12.5% THC) led to an acute decrease in speed in young adults.•There was no clear effect of smoked cannabis on lateral control.•There was little evidence of residual effects of ...smoked cannabis on driving performance.
Although driving under the influence of cannabis is increasingly common among young adults, little is known about residual effects on driver behavior. This study examined acute and residual effects of smoked cannabis on simulated driving performance of young cannabis users.
In this double-blind, placebo-controlled, parallel-group randomized clinical trial, cannabis users (1–4 days/week) aged 19–25 years were randomized with a 2:1 allocation ratio to receive active (12.5% THC) or placebo (0.009% THC) cannabis in a single 750 mg cigarette. A median split (based on whole-blood THC concentrations at the time of driving) was used to divide the active group into low and high THC groups. Our primary outcome was simulated driving performance, assessed 30 min and 24 and 48 h after smoking. Secondary outcomes included blood THC concentrations, subjective drug effects, and heart rate.
Ninety-six participants were randomized, and 91 were included in the final analysis (30 high THC, 31 low THC, 30 placebo). Mean speed (but not lateral control) significantly differed between groups 30 min after smoking cannabis (p ≤ 0.02); low and high THC groups decreased their speed compared to placebo. Heart rate, VAS drug effect and drug high increased significantly immediately after smoking cannabis and declined steadily after that. There was little evidence of residual effects in any of the measures.
Acutely, cannabis caused decreased speed, increased heart rate, and increases in VAS drug effect and drug high. There was no evidence of residual effects on these measures over the two days following cannabis administration.
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