Plasma concentration of CORT and 5HT in non-smokers, smokers and patients with COPD.

<p>(A) The level of plasma CORT increased slightly in smokers but was significantly reduced on patients with COPD relative to non-smokers and smokers (current/ex-smokers). (B) COPD patients show lower 5HT concentration than non-smokers and smokers. The level of plasma 5HT was not affected in smokers when compared with non-smokers. Data are shown as mean ± SEM (n = 10–12 subjects per group). **<i>P</i><0.01 significant when non-smokers were compared to patients with COPD; ^{# #}<i>P</i><0.01 significant when smokers were compared to patients with COPD.</p

Daily rhythms of plasma CORT and 5HT in mice exposed to sub-chronic (10 day) air or CS.

<p>Mice were exposed to CS for 10 days, and plasma samples were collected at 6-h interval for 48 h (starting at ZT12) beginning 24 h after the last exposure. Plasma levels of (A) CORT and (B) 5HT were determined by ELISA. Gray shading indicates the dark phase (ZT12 to ZT24). Data from air- and CS-exposed mice are shown as mean ± SEM (n = 3 mice per group). Data were fit with non-linear regression (multi-order polynomial) analyses. **<i>P</i><0.01 significant compared to air-exposed mice at ZT12; ***<i>P</i><0.001 significant compared to air-exposed mice at ZT6.</p

Daily rhythms of plasma CORT and 5HT in mice exposed to chronic (6 month) air or CS.

<p>Mice were exposed to chronic CS for 6 months and plasma samples were collected every 6-h interval (ZT0, ZT6, ZT12, ZT18 and ZT24) after 24 h of last CS exposure. Plasma levels of (A) CORT and (B) 5HT and were determined by ELISA. Gray shading indicates the dark phase (ZT12 to ZT24). Data from air- and CS-exposed mice are shown as mean ± SEM (n = 3–4 mice per group). Data were analyzed with non-linear regression (multi-order polynomial) analyses. *<i>P</i><0.05 significant compared to air-exposed mice at ZT0; *<i>P</i><0.05 significant compared to CS-exposed mice at ZT24; ***<i>P</i><0.001 significant compared to CS-exposed mice at ZT18.</p

Influence of age on daily rhythms of plasma 5HT in air or CS-exposed mice.

<p>Adult mice (8–10 weeks old at start of CS exposure) were exposed to air or CS for 3 days (young), 10 days (young) and 6 months (middle aged). Plasma levels of 5HT were determined by ELISA. Gray shading indicates the dark phase (ZT12 and ZT18). Data from air- and CS-exposed mice are shown as mean ± SEM (n = 3–7 mice per group). Data were analyzed with non-linear regression (multi-order polynomial) analyses. *<i>P</i><0.05; **<i>P</i><0.01; ***<i>P</i><0.001 significant compared to 3 days air- (ZT0–ZT18) or CS- (ZT6) exposed mice; ^{+ +}<i>P</i><0.01; ^{+ + +}<i>P</i><0.001 significant compared to 3 days air-exposed mice (ZT0–ZT18); ^{# #}<i>P</i><0.01; ^{# # #}<i>P</i><0.001 significant compared to 10 days air- (ZT0) or CS- (ZT6) exposed mice.</p

Influence of age on daily rhythms of plasma CORT in air or CS-exposed mice.

<p>Adult mice (8–10 weeks old at start of CS exposure) were exposed to air or CS for 3 days (young), 10 days (young) and 6 months (middle aged). Plasma levels of CORT were determined by ELISA. Gray shading indicates the subjective dark phase (ZT12 and ZT18). Data from air- and CS-exposed mice are shown as mean ± SEM (n = 3–7 mice per group). Data were analyzed with non-linear regression (multi-order polynomial) analyses. ⁺<i>P</i><0.05; ^{+ + +}<i>P</i><0.001 significant compared to 3 days air- or CS-exposed mice; ^{# #}<i>P</i><0.01; ^{# # #}<i>P</i><0.001 significant compared to 10 days air-exposed mice.</p

Daily rhythms of plasma CORT and 5HT in mice exposed to acute (3 day) air or CS.

<p>Mice were exposed to acute CS during the light phase for 3 days, and plasma samples were collected at every 6-h interval (ZT0, ZT6, ZT12, and ZT18) beginning 24 h after the last exposure. Plasma levels of (A) CORT and (B) 5HT were determined by ELISA. Gray shading indicates the subjective dark phase (ZT12 to ZT24). Data were fit with non-linear regression (multi-order polynomial) analyses. Data are shown as mean ± SEM (n = 3–7 mice per group). **<i>P</i><0.01 significant compared to CS-exposed mice at ZT6.</p

Center of gravity (COG) values for plasma concentration of CORT and 5HT as determined by CircWave analysis in 3 days, 10 days and 6 month air or CS exposed mice.

<p>Data are shown as mean ± SEM (n = 3–7 per group).</p><p>*<i>P</i><0.05, **<i>P</i><0.01, significance of rhythmicity as determined by CircWave analysis in air or CS exposed mice.</p

General clinical characteristics of non-smokers, smokers and COPD patients.

<p>M:F: Male to Female ratio; FEV₁: Forced Expiratory Volume in one second; ICS: inhaled corticosteroids.</p

Significant downregulated genes in the mycHIF3α expressing lungs.

<p>Significant downregulated genes in the mycHIF3α expressing lungs.</p

Normal differentiation of distal epithelial cells in mycHIF3α transgenic lungs.

<p>The site and expression pattern of T1α (A and B), Lpcat1 (C and D) and Ki67 (E and F) are comparable between control and mycHIF3α double transgenic lungs at gestational age E18.5. Scale bars: 100 µm</p