Inflammatory Response as a Mechanism of Perinatal Programming: Long-term Impact on Pulmonary and Renal Function?

RATIONALE: Temporal changes in the fetal environment, such as malnutrition and placental insufficiency induce intrauterine growth restriction (IUGR) and lead to a permanent changes of physiological processes later in life. Interestingly, epidemiological studies demonstrated an impairment of lung and renal function in young infants subsequent to IUGR. Complementary, experimental studies showed that IUGR induces a perinatal programming of the developing lung with persisting impairment of pulmonary structure and function. Besides IUGR, early postnatal hyperalimentation (pHA) is discussed as a crucial factor of IUGR-associated diseases. Both extracellular matrix (ECM) and inflammatory processes have been shown to be dysregulated following IUGR and early pHA. However, the underlying molecular mechanisms of IUGR-associated diseases and the potential linkage of ECM and inflammation have not been addressed so far. Therefore, the ultimate goal of this project was to elucidate the role of regulation of ECM and inflammatory cytokines subsequent to IUGR and early pHA. AIMS: There are three specific aims: (1) to analyze the role of the TGF-β signaling in lung development subsequent to IUGR, (2) to determine the regulation of inflammatory cytokines and ECM-molecules in lungs subsequent to IUGR, and (3) to characterize the pathomechanistic role of early pHA using the example of the kidney. METHODS: Two simultaneous sets of animal experiments were used. One animal model addressed pre- and postnatal nutritional intervention, the other was restricted to postnatal interventions only: (A) IUGR was induced in Wister rats by isocaloric low protein diet (8% casein; IUGR) during gestation. The control group received normal protein diet (17% casein; Co). At birth the litter size was reduced to 6 male pups to induce early pHA. During lactation the mothers of both groups were fed standard chow. (B) Early pHA was induced by litter size reduction to 6 (LSR6) or 10 (LSR10) male neonates. Home-cage control (HCC; mean litter size of 16) animals without any postnatal manipulation during lactation were included. At postnatal day (P) 28 as well as P70 animals underwent whole body plethysmography and in addition metabolic cages at P70. Serum and samples of lungs and kidney were obtained at P1, P12, P21, P42, and P70 for mRNA extraction, protein extraction as well as histological analyses. RESULTS: Both respiratory system resistance and compliance were impaired subsequent to IUGR at P28; this impairment was even more significant at P70. (1) These changes were accompanied by persistent attenuated activity of the TGF-β signaling, assessed by phosphorylation of Smad2 and Smad3. Expression analysis of TGF-β-regulated ECM components in the lungs of IUGR animals at P1, such as collagen I, elastin, and tenascin N, revealed a significant deregulation. Consistently, in vitro inhibition of TGF-β signaling in NIH/3T3, MLE 12 and endothelial cells by adenovirus-delivered Smad7 demonstrated a direct effect on the expression of ECM components. Interestingly, however, not just a deregulation of ECM components was detected at P1, but also attenuated apoptotic processes, e.g. decreased cleavage of PARP. (2) Since the TGF-β signaling has potent anti-inflammatory effects, we next determined the dynamic expression of pro-inflammatory and pro-fibrotic markers as well of ECM components in the lung subsequent to IUGR at P1, P42 and P70. The expression of ECM components and metabolizing enzymes was markedly deregulated and the deposition of collagen I was strikingly increased at P70. Concomitantly to the pro-fibrotic processes in the lung subsequent to IUGR, the expression of inflammatory cytokines and both the activity and the expression of target genes of Stat3 signaling were dynamically regulated, with unaltered or decreased expression at P1 and significantly increased expression art P70. (3) Assessment of renal function at postnatal day 70 revealed decreased glomerular filtration rate, proteinuria, and increased fractional sodium and potassium secretion following early pHA (LSR6). Moreover, the deposition of ECM molecules, such as collagen I, was increased. Interestingly, despite the elevated expression of pro-inflammatory leptin and IL-6 expression the phosphorylation of Stat3 and ERK1/2 in the kidney, however, was decreased after LSR6. In accordance, neuropeptide Y (NPY) gene expression – sympathetic co-neurotransmitter regulated by Stat3 signaling – was down-regulated. In accordance, suppressor of cytokine signaling (SOCS)3 protein expression, an inhibitor of Stat3 and Erk1/2 signaling, was strongly elevated and colocalized with NPY. Interestingly, NPY is co- localized with SOCS3 in the distal tubules in the cortex and outer medulla, and in the proximal tubules, but no expression of SOCS3 was detectable in glomeruli. CONCLUSION: Taken together, IUGR has a direct and strong negative impact on respiratory resistance and compliance of the lung. There are two major underlying mechanisms linking IUGR and deregulation of ECM: first, the attenuated TGF-β signaling during late lung development; and second, the increased expression of inflammatory cytokines subsequent to IUGR. In addition, the missing anti-inflammatory effect of TGF-β signaling could contribute to the increased inflammatory response following IUGR. Furthermore we demonstrated that early pHA leads to organ-intrinsic increased expression of NPY via a postreceptor-leptin-receptor leptin resistance. This leptin resistance could contribute to the observed profibrotic processes, and ultimately to a long-term impairment of renal function. Thus, both IUGR and early postnatal hyperalimentation have a strong impact on perinatal programming of multi-organ inflammatory response

Topology of 2D and 3D Rational Curves

In this paper we present algorithms for computing the topology of planar and space rational curves defined by a parametrization. The algorithms given here work directly with the parametrization of the curve, and do not require to compute or use the implicit equation of the curve (in the case of planar curves) or of any projection (in the case of space curves). Moreover, these algorithms have been implemented in Maple; the examples considered and the timings obtained show good performance skills.Comment: 26 pages, 19 figure

Involutions of polynomially parametrized surfaces

We provide an algorithm for detecting the involutions leaving a surface defined by a polynomial parametrization invariant. As a consequence, the symmetry axes, symmetry planes and symmetry center of the surface, if any, can be determined directly from the parametrization, without computing or making use of the implicit representation. The algorithm is based on the fact, proven in the paper, that any involution of the surface comes from an involution of the parameter space (the real plane, in our case); therefore, by determining the latter, the former can be found. The algorithm has been implemented in the computer algebra system Maple 17. Evidence of its efficiency for moderate degrees, examples and a complexity analysis are also given

Symmetry Detection of Rational Space Curves from their Curvature and Torsion

We present a novel, deterministic, and efficient method to detect whether a given rational space curve is symmetric. By using well-known differential invariants of space curves, namely the curvature and torsion, the method is significantly faster, simpler, and more general than an earlier method addressing a similar problem. To support this claim, we present an analysis of the arithmetic complexity of the algorithm and timings from an implementation in Sage.Comment: 25 page

Decoherent time-dependent transport beyond the Landauer-B\"uttiker formulation: a quantum-drift alternative to quantum jumps

We present a model for decoherence in time-dependent transport. It boils down into a form of wave function that undergoes a smooth stochastic drift of the phase in a local basis, the Quantum Drift (QD) model. This drift is nothing else but a local energy fluctuation. Unlike Quantum Jumps (QJ) models, no jumps are present in the density as the evolution is unitary. As a first application, we address the transport through a resonant state $\left\vert 0\right\rangle$ that undergoes decoherence. We show the equivalence with the decoherent steady state transport in presence of a B\"{u}ttiker's voltage probe. In order to test the dynamics, we consider two many-spin systems whith a local energy fluctuation. A two-spin system is reduced to a two level system (TLS) that oscillates among $\left\vert 0\right\rangle$ $\equiv$ $\left\vert \uparrow \downarrow \right\rangle$ and $\left\vert 1\right\rangle \equiv$ $\left\vert \downarrow \uparrow \right\rangle$. We show that QD model recovers not only the exponential damping of the oscillations in the low perturbation regime, but also the non-trivial bifurcation of the damping rates at a critical point, i.e. the quantum dynamical phase transition. We also address the spin-wave like dynamics of local polarization in a spin chain. The QD average solution has about half the dispersion respect to the mean dynamics than QJ. By evaluating the Loschmidt Echo (LE), we find that the pure states $\left\vert 0\right\rangle$ and $\left\vert 1\right \rangle$ are quite robust against the local decoherence. In contrast, the LE, and hence coherence, decays faster when the system is in a superposition state. Because its simple implementation, the method is well suited to assess decoherent transport problems as well as to include decoherence in both one-body and many-body dynamics.Comment: 10 pages, 5 figure