Mucosal-Associated Invariant T Cell Deficiency in Chronic Obstructive Pulmonary Disease

<p>Mucosal-associated invariant T (MAIT) cells have been reported to play an important role in mucosal immunity. However, little is known about the roles of MAIT cells in chronic obstructive pulmonary disease (COPD). The aims of this study were to examine the levels of circulating MAIT cells and their subsets in COPD patients and to investigate the potential relationship between clinical parameters and MAIT cell levels. Forty-five COPD patients and 57 healthy control subjects were enrolled in the study. Circulating MAIT cells and their subset levels in the peripheral blood were measured by flow cytometry. Disease grades were classified according to the GOLD criteria for the assessment of severity of COPD. Circulating MAIT cell levels were found to be significantly reduced in COPD patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets. Interestingly, elevated serum C-reactive protein level and reduced FEV₁/FVC ratio were associated with MAIT cell deficiency in COPD patients. Furthermore, the circulating MAIT levels were found to be significantly lower in patients with moderate to severe COPD than in patients with mild COPD. Our data shows that MAIT cells are numerically deficient in the peripheral blood of patients with COPD. In addition, this MAIT cell deficiency was found to reflect inflammatory activity and disease severity. These findings provide important information for monitoring the changes in MAIT cell levels and for predicting the prognosis during the disease course.</p

Piceatannol reduces extracellular matrix (ECM) protein and fibrosis marker protein expression in the UUO kidney.

<p>One day after UUO surgery, the mice received an intraperitoneal injection of vehicle or piceatannol (50 mg/kg/day) for 2 weeks. (A) Protein lysates from kidney tissues were prepared and were analyzed using western blotting. Anti-collagen 1, fibronectin, α-SMA, and CTGF antibodies were used. GADPH was used as a loading control. Representative immunoblots. (B-E) Protein levels were quantified using densitometry. The data are expressed as the means ± SD of the mice (n = 6 per group). ***<i>P</i><0.001 compared with the contralateral kidney. ^##<i>P</i><0.01 and ^###<i>P</i><0.001 compared with the UUO kidney.</p

Piceatannol attenuates phosphorylated p38 MAPK expression in the UUO kidney.

<p>(A) Kidney lysates were used for western blot analysis. Antibodies against p-JNK2 (Thr183/Tyr185), JNK2, p-ERK1 (Thr202/Tyr204), ERK1, p-p38 (Thr180/Tyr182), and p38 were used. GAPDH was used as a loading control. (B-E) Quantification analysis was performed using densitometry. The data are expressed as the means ± SD of the mice (n = 6 per group). *<i>P</i><0.05, **<i>P</i><0.01, and ***<i>P</i><0.001 compared with the contralateral kidney. ^#<i>P</i> <0.05 compared with the UUO kidney. NS indicates not significant compared with the UUO kidney.</p

Piceatannol decreases renal fibrosis in the UUO kidney.

<p>(A-B) One day after UUO surgery, mice were received an intraperitoneal injection of vehicle or piceatannol (50 mg/kg/day) for 2 weeks. (A) Masson’s trichrome staining was performed to examine interstitial fibrosis: contralateral + vehicle, contralateral + piceatannol, UUO + vehicle, and UUO + piceatannol. Scale bar is 100 μm. (B) Immunofluorescent staining using anti-collagen type I antibody. A representative photomicrograph is shown. Scale bar is 100 μm.</p

Piceatannol suppresses renal fibrosis by downregulation of the p38-MAPK/HDAC4/5 pathway.

<p>Fibrotic stress such as UUO can induce TGF-β1 expression, which causes phosphorylation and upregulation of Smad2/3 or MAPK (JNK2, ERK1/2, or p38) protein expression. It also increases the expression of class II HDACs (HDAC4/5). Piceatannol attenuates the activation of p38-MAPK signaling and the increased HDAC4/5 expression, but not the activation of the TGF-β1/Smad3 signaling pathway. However, whether a direct association between HDAC4/5 and MAPK signaling or between HDAC4/5 and renal fibrosis exists remains unknown. TβRII and TβRI indicate TGFβ receptor II and TGFβ receptor I, respectively.</p

Pharmacological effects of piceatannol and resveratrol on <i>in vivo</i> models of renal diseases.

<p>Pharmacological effects of piceatannol and resveratrol on <i>in vivo</i> models of renal diseases.</p

Piceatannol reduces the mRNA level of fibrosis-related genes in the UUO kidney.

<p>(A-D) One day after UUO surgery, the mice received an intraperitoneal injection of vehicle or piceatannol (50 mg/kg/day) for 2 weeks. The transcription level of collagen type I (collagen type I), fibronectin, alpha smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF) was determined using qRT-PCR in kidney tissues from UUO mice treated with vehicle or piceatannol. The data are expressed as the means ± SD of the mice (n = 6 per group). ***<i>P</i><0.001 compared with the contralateral kidney. ^#<i>P</i><0.05 and ^##<i>P</i><0.01 compared with the UUO kidney.</p

Piceatannol does not suppress TGF-β1-Smad signaling in the UUO kidney.

<p>(A) Kidney lysates were used for western blot analysis. Antibodies against TGF-β1, p-Smad3 (Ser423/425), Smad3, Smad2, and Smad4 were used. GAPDH was used as a loading control. (B-E) Quantification analysis was performed using densitometry. The data are expressed as the means ± SD of the mice (n = 6 per group). **<i>P</i><0.01 and ***<i>P</i><0.001 compared with the contralateral kidney. NS indicates not significant compared with the UUO kidney.</p

HDAC1 protein expression is upregulated in the UUO kidney.

<p>(A) Kidney protein lysates were analyzed using western blotting. Antibodies against HDAC1, HDAC2, HDAC3, and HDAC8 were used. GAPDH was used as a loading control. (B-E) Quantification analysis was performed using densitometry. The data are expressed as the means ± SD of the mice (n = 6 per group). *<i>P</i><0.05 and ***<i>P</i><0.001 compared with the contralateral kidney. NS indicates not significant.</p

Piceatannol attenuates the expression of UUO-induced renal HDAC5/HDAC6 protein.

<p>(A) Kidney lysates were used for western blot analysis. Antibodies against HDAC4, HDAC5, HDAC6, and HDAC10 were used. GAPDH was used as a loading control. (B-E) Quantification analysis was performed using densitometry. The data are expressed as the means ± SD of the mice (n = 6 per group). *<i>P</i><0.05 and ***<i>P</i><0.001 compared with the contralateral kidney. ^###<i>P</i> <0.001 compared with the UUO kidney. NS indicates not significant compared with the UUO kidney.</p