Rodent Models Of Chronic Inflammation Research Articles

Impaired mitochondrial degradation by autophagy in the skeletal muscle of the aged female interleukin 10 null mouse

Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondrial clearance is a process to dampen inflammation and is a critical pre-requisite to mitobiogenesis. The combined effect of aging and chronic inflammation on mitochondrial degradation by autophagy is understudied. In interleukin 10 null mouse (IL-10tm/tm), a rodent model of chronic inflammation, we studied the effects of aging and inflammation on mitochondrial clearance. We show that aging in IL-10tm/tm is associated with reduced skeletal muscle mitochondrial death signaling and altered formation of autophagosomes, compared to age-matched C57BL/6 controls. Moreover, skeletal muscles of old IL-10tm/tm mice have the highest levels of damaged mitochondria with disrupted mitochondrial ultrastructure and autophagosomes compared to all other groups. These observations highlight the interface between chronic inflammation and aging on altered mitochondrial biology in skeletal muscles.

Tumor Necrosis Factor-α Induces Aortic Intima-Media Thickening via Perivascular Adipose Tissue Inflammation

Background/Aims: Neointimal thickening results from inflammation in association with vascular smooth muscle cell (VSMC) proliferation. We studied the role of perivascular adipose tissue (PVAT) on VSMC proliferation and intima-media thickening (IMT) in a rodent model of chronic inflammation. Methods: The abdominal aorta and surrounding PVAT of tumour necrosis factor (TNF)-α-injected mice were examined 28 days after administration. Plasma and PVAT cytokines were measured with Milliplex™ assays. Inflammatory cells were examined with immunofluorescence. Expression of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 was examined with immunohistochemistry, immunoblotting and zymography. IMT was determined. Cell proliferation and TGF-β1 mRNA levels were examined after treating VSMC with PVAT homogenates ± MMP-2 inhibitors (batimastat, ARP 100 or TIMP-2) and SB-431542, a selective inhibitor of the TGF-β-type 1 receptor. Results: Significant increases in CD3, CD68, neutrophils, vascular cell adhesion molecule-1 and MMP-2 in PVAT, and TGF-β1 and IMT of the aorta of TNF-α-injected mice were observed. PVAT of TNF-α-injected mice significantly up-regulated TGF-β1 and increased cell proliferation in a dose-dependent manner and was attenuated by SB-431542, batimastat, ARP 100 and TIMP-2. Conclusions: Our study shows that chronic PVAT inflammation leads to MMP-mediated increase in TGF-β1 and hence VSMC proliferation.

Investigation of a chronic inflammation model in swine

Previous research demonstrated slow‐release lipopolysaccharide (LPS) pellets could induce a chronic inflammatory response in rodents. The objective of this preliminary study was to translate this rodent model of chronic inflammation into swine. A dose‐response study with repeated measures was performed using 12 barrows (~ 100 kg; three per group). The four treatments groups were: non‐surgical controls, placebo (pellet with matrix only), and pellets with LPS designed to release at a rate of 2.5 or 5.0 μg/kg/d. Food intake and behavior were monitored daily. Rectal temperatures and blood samples were taken on days 0, 1, 2, 3, and 7 post‐implantation. Implantation of the pellets did not induce lethargy and vomiting in the pigs thereby demonstrating the LPS dosages were safe to use in swine. Temperature was increased (P<0.05) by LPS on day 1 but returned to baseline levels by day 2. LPS caused an increase (P<0.05) in neutrophils and a decrease (P<0.05) in lymphocytes indicating the induction of an inflammatory response. Neutrophil and lymphocyte counts returned to baseline levels by day 7. No differences (P>0.05) were observed between the two dosages of LPS. The results of this preliminary study indicate the use of slow‐release LPS pellets are safe and efficacious to use in generating a low‐grade inflammatory response in swine. Supported by: SD Agricultural Experiment Station and the SDSU Research and Support Fund

Opioid Peptides Endomorphin‐1 and Endomorphin‐2 in the Immune System in Humans and in a Rodent Model of Inflammation

Endomorphin (EM)-1 and EM-2 are tetrapeptides with high affinity and selectivity for the micro-opioid receptor. We have utilized specific radioimmunoassays to characterize EM-1 and EM-2 in immune tissues from normal human subjects and from rats with adjuvant arthritis (AA). PBLs from three normal human subjects contained 248, 13, and 303 pg EM-1 per 100 million cells, whereas EM-2 was measured in two subjects at 69 and 588 pg per 100 million cells. In AA rats, EM-1 (but not EM-2) contents in the spleen and thymus were elevated compared with levels in tissues from non-AA controls. EM-1 was detectable in five of eight samples of synovial tissue from inflamed hind paws, whereas EM-2 was detectable in two of eight synovial extracts. Neither EM-1 nor EM-2 were detectable in synovial tissue from non-AA rats. To our knowledge, this is the first report of endomorphins in normal human immune cells. Increased endomorphin expression or uptake in peripheral tissues in a rodent model of chronic inflammation provides potential for endomorphins to selectively modulate chronic inflammation in mammals.

Alterations in Hypothalamic–Pituitary–Adrenal Function Correlated with the Onset of Murine SLE in MRL +/+ and lpr/lpr Mice

Systemic lupus erythematosus (SLE) is a spontaneously occurring, chronic autoimmune disease that can manifest neuropsychiatric abnormalities. The pathways mediating these central changes are not known; however, neuroendocrine alterations associated with inflammation may play a role. Predisposition to and progression of autoimmune disease has been associated with altered hypothalamic–pituitary–adrenal (HPA) function and inflammation has been reported to alter hypothalamic regulation of HPA responses. We investigated whether disease progression in a murine model of systemic lupus erythematosus (MRL +/+. MRL lpr/lpr) resulted in altered expression of HPA regulatory peptides at the level of the hypothalamus and how these alterations related to circulating levels of corticosterone, corticosterone binding globulin, and autoantibody titers. We report that as MRL +/+ and MRL lpr/lpr mice age and circulating levels of autoantibodies increase, there is a decrease in hypothalamic CRH mRNA expression and finally an increase in AVP mRNA expression. We also report that associated with increased autoantibody levels, disease progression, and altered hypothalamic peptide expression there is an increase in circulating levels of corticosterone and a trend for levels of corticosterone binding globulin to decrease. Our data complement previous observations of altered peptidergic regulation of the HPA axis and increased HPA activity during chronic inflammation in exogenously induced rodent models of chronic inflammation and indicate that similar processes may occur in spontaneous murine models of SLE.