Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function

Occludin S408 phosphorylation regulates interactions between occludin, ZO-1, and select claudins to define tight junction molecular structure and barrier function

Nitric Oxide Prevents Alveolar Senescence and Emphysema in a Mouse Model

Nω-nitro-L-arginine methyl ester (L-NAME) treatment induces arteriosclerosis and vascular senescence. Here, we report that the systemic inhibition of nitric oxide (NO) production by L-NAME causes pulmonary emphysema. L-NAME-treated lungs exhibited both the structural (alveolar tissue destruction) and functional (increased compliance and reduced elastance) characteristics of emphysema development. Furthermore, we found that L-NAME-induced emphysema could be attenuated through both genetic deficiency and pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1). Because PAI-1 is an important contributor to the development of senescence both in vitro and in vivo, we investigated whether L-NAME-induced senescence led to the observed emphysematous changes. We found that L-NAME treatment was associated with molecular and cellular evidence of premature senescence in mice, and that PAI-1 inhibition attenuated these increases. These findings indicate that NO serves to protect and defend lung tissue from physiological aging.</p

Nitric oxide prevents alveolar senescence and emphysema in a mouse model.

Nω-nitro-L-arginine methyl ester (L-NAME) treatment induces arteriosclerosis and vascular senescence. Here, we report that the systemic inhibition of nitric oxide (NO) production by L-NAME causes pulmonary emphysema. L-NAME-treated lungs exhibited both the structural (alveolar tissue destruction) and functional (increased compliance and reduced elastance) characteristics of emphysema development. Furthermore, we found that L-NAME-induced emphysema could be attenuated through both genetic deficiency and pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1). Because PAI-1 is an important contributor to the development of senescence both in vitro and in vivo, we investigated whether L-NAME-induced senescence led to the observed emphysematous changes. We found that L-NAME treatment was associated with molecular and cellular evidence of premature senescence in mice, and that PAI-1 inhibition attenuated these increases. These findings indicate that NO serves to protect and defend lung tissue from physiological aging

L-NAME-induced senescence in lung tissue.

<p><b>(A)</b> ATLR measurements from 8 week-treated lungs. <b>(B-D)</b> qRT-PCR data from 1 week-treated lungs evaluating the senescence markers <b>(B)</b> p16^Ink4a, <b>(C)</b> p53, and <b>(D)</b> p21. <b>(A)</b> *P = 0.007. n = 12. <b>(B-D)</b> *P = 0.02. n = 7–11. Data are mean ± SD.</p

Effects of L-NAME on lung functional dynamics.

<p>Measurements for <b>(A)</b> compliance, <b>(B)</b> static compliance, <b>(C)</b> elastance, and <b>(D)</b> static elastance demonstrate that L-NAME-treated lungs have the functional characteristics of emphysema. Both genetic and pharmacologic inhibition of PAI-1 protected mice from lung dysfunction. <b>(A)</b> and <b>(C)</b> *P = 0.002, #P = 0.02, $P = 6.3x10^-6. <b>(B)</b> and <b>(D)</b> *P = 0.004, #P = 0.01. Data are mean ± SD. n = 6–7.</p

L-NAME treatment causes emphysema.

<p>Lung tissue sections from <b>(A)</b> WT, <b>(B)</b> WT + L-NAME, <b>(C)</b> WT + L-NAME + TM5441, and <b>(D)</b> PAI-1-/- + L-NAME demonstrate that L-NAME causes significant alveolar destruction and that PAI-1 inhibition is partially protective against this. <b>(E)</b> Mean linear intercept quantifications. *P = 0.0002, #P = 0.04, $P = 0.009. Data are mean ± SD. n = 11–13.</p