Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease

Figures

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  Figure 1. General Characteristics of control and Dp(16Lipi-Zfp295)1Yey mice. There were no differences observed in sex among offspring between littermate controls and Dp16 mice. (a) Compared to controls (n = 128 males, 116 females), Dp16 mice (n = 51 males, 56 females) display reduced body weight and are shorter in length (controls n = 9 males, 13 females, Dp16 n = 9 males, 14 females) across the lifespan. (b) In a selected cohort (n = six controls, six Dp16), Dp16 mice required more ketamine/xylazine to reach an anesthetized state. * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.

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  Figure 2. Compared to control mice (n = 6), Dp16 mice (n = 6) circulate a unique profile of blood plasma cytokines and chemokines. Higher levels were observed for tumor necrosis (TNF)-α, interferon (IFN)-γ, keratinocyte chemoattractant/human growth regulated oncogene (KC-GRO, also known as chemokine C-X-C motif ligand 1, CXCL1), interleukin (IL)-2, IL-5, IL-6, IL-10, and IL-12p70. No differences were found in plasma IL-1beta or IL-4. ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.

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  Figure 3. Lung gene expression differs between control mice and Dp16 mice. (a). Representative result from RNA seq experiment showing increased IFNAR1 mRNA in Dp16 mice lung (n = 6 controls, n = 6 Dp16). (b). Representative results from quantitative reverse transcriptase polymerase chain reaction showing increased mRNA levels of IFNAR1, IFNGR2, and IL-10Rb in lungs of Dp16 mice vs. controls. (n = 7 males 8 females controls, n = 7 males 8 females Dp16). (c). Representative IFNAR1 immunoblot, GAPDH immunoblot, and bar graphs summarizing blot densitometric data. Compared to controls, lungs from Dp16 male mice showed decreased expression of IFNAR1 protein and increased phospho-STAT3. Compared to control mice, lungs from Dp16 female mice showed increased protein expression of STAT3 and pSTAT3. IFNGR2 protein was not detectable by immunoblot in any lung samples. (n = 6 males 6 females controls, n= 6 males 6 females Dp16). (d). The lungs of Dp16 male mice express significantly less PAFR protein compared to controls. (n = 6 males 6 females controls, n = 6 D males 6 females p16). * = p < 0.05; ** = p < 0.01.

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  Figure 4. Lungs of Dp16 mice are functionally and structurally different than control mice lungs. (a). At all measurement onset pressures (PEEPs), elastance is significantly increased in Dp16 mice (n = 7 males 6 females) compared to controls (n = 15 males 10 females). (b). At (only) PEEP = 9 cm H2O)/mL, lung airway resistance is increased in male Dp16 mice compared to controls. (c). There is no significant difference in inspiratory capacity in Dp16 mice compared to controls. (d). MLI analysis reveals a 1.3-fold increase in mean linear intercept (MLI) of lung parenchyma in Dp16 mice compared to controls (bar graph, left). Representative images of hematoxylin and eosin stained sections from control (left) and Dp16 (right). Black arrows indicate regions of alveolar simplification (e). Compared to controls (n = 3 males 3 females), Dp16 mice (n = 3 males 3 females) display numerous follicularized bronchus-associated lymphoid tissues (left representative image of a hematoxylin and eosin stained section, black arrows) and which contain discrete zones of T cells (red) and B cells (green) (white arrows, right representative image of a immunofluoresecent stained image; blue = DAPI stained nuclei).…

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  Figure 5. Analyses of hearts from controls and Dp16 mice. (a). Gravimetric data showing no differences in RV myocardial water content (wet weight minus dry weight/dry weight) in Dp16 mice (n = 7 males 7 females) vs. controls (n = 7 males 8 females). (b). Fulton scores (right ventricle mass/left ventricle mass plus interventricular septum mass) showing absence of right ventricular hypertrophy in Dp16 mice (n = 10 males 10 females) and controls (n = 13 males 9 females). (c). Bar graphs summarizing densitometric data from immunoblots of RVs from control (n = 6 males 6 females) and Dp16 (n = 6 males 6 female) mice. IFNAR1 and IL-10Rb were significantly decreased in male Dp16 mice vs. controls. * = p < 0.05.