Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16 −/− mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16 −/− mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.

Chronic hyperendothelinemia reduces the pulmonary vasodilator reserve in response to nitric oxide. Correction by an antioxidant and L-NNA suggests that this relates to increased production of reactive oxygen species, which may have clinical relevance for conditions associated with chronic increase of ET. Further studies are required to determine if, in the long term, this could contribute to the development of pulmonary hypertension.

-Vascular hyperplasia may be involved in the remodeling of vasculature. It was unknown whether there were genetic determinants for aortic smooth muscle cell number (SMCN) and, if so, whether they acted independently of those for blood pressure (BP). To unravel this issue, we utilized congenic strains previously constructed for BP studies. These strains were made by replacing various chromosome 2 segments of the Dahl salt-sensitive (S) rat with those of the Milan normotensive rat (MNS). We measured and compared SMCN in aortic cross-sectional areas and BPs of these strains. Consequently, a quantitative trait locus (QTL) for SMCN was localized to a chromosome region not containing a BP QTL, but harboring the locus for the angiotensin II receptor AT1B (Agtr1b). Agtr1b became a candidate for the SMCN QTL because 1) two significant mutations were found in the coding region between S and all congenic strains possessing the MNS alleles, and 2) contractile responses to angiotensin II were significantly and selectively reduced in congenic rats harboring the MNS alleles of the SMCN QTL compared with S rats. The current investigation presents the first line of evidence that a QTL for aortic SMCN exists, and it acts independently of QTLs for BP. The relevant congenic strains developed therein potentially provide novel mammalian models for the studies of vascular remodeling disorders. functional genomics; angiotensin II receptor AT1B; aortic hyperplasia; vasoreactivity; congenic strains HYPERTROPHY AND/OR VASCULAR HYPERPLASIA may contribute to the elasticity/rigidity of the blood vessel and peripheral vascular resistance. Although cardiac hypertrophy and hypertension were sometimes associated, there were indications that genes for blood pressure (BP) and left ventricular hypertrophy (LVH) could be separated in hypertensive models (3,22). LVH can be determined by genes from normotensive rats independently of hypertension (28).As for a relationship between hypertension and hyperplasia, the initial evidence indicated that the cultured aortic smooth muscle cells (SMC) proliferated faster (i.e., hyperplasia) in the spontaneously hypertensive rats (SHR) than in the Wistar Kyoto rats (WKY) (21, 41). These findings suggested a link between hypertension and the SMC proliferation. Since then, a large body of evidence has been accumulated on their associations (5,14,21,23,27,38). On the basis of these observations, one would expect that a higher SMC proliferation might correlate with a higher BP. Nevertheless, there was one genetic study reporting that hypertension was not associated with the growth of skin fibroblast in a F2 cross between SHR and WKY (20). This is not surprising, because an association between BP and the SMC growth in these two strains could simply be accidental, not causal, one way or the other.To date, it has remained unclear whether there are quantitative train loci (QTLs) determining vascular SMC number and, if so, whether mechanisms determining hypertension and vascular hyperplasia could be separated. Our current ...

This is an Accepted Manuscript for the Microscopy and Microanalysis 2020 Proceedings. This version may be subject to change during the production process.

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