Inhaled nitric oxide is a targeted pulmonary vasodilator that improves clinical outcomes for newborn patients with persistent pulmonary hypertension of the newborn, and may be effective in treating some premature patients with acute respiratory distress syndrome or lung disease of prematurity. Nitric oxide is now recognized as playing an important role in the regulation of diverse physiological processes. However, the pharmacological properties of inhaled nitric oxide are not easy to separate from its toxicological effects. For example, the intended effect of inhaled nitric oxide, vasodilation in the lung, is mediated, in part, by increased cellular cyclic GMP (cGMP). However, increased cGMP can also interfere with normal cellular proliferation. Nitric oxide has also been shown to cause DNA strand breaks and/or base alterations that are potentially mutagenic. Inhaled nitric oxide can rapidly react with oxygen in the lung to form nitrogen dioxide, which is a potent pulmonary irritant. Nitric oxide also reacts with superoxide anion to form peroxynitrite, a cytotoxic oxidant that can interfere with surfactant functioning. The overall effect of inhaled nitric oxide in potentiating or attenuating inflammation and oxidative damage in diseased lung is dependent on the dose administered. Furthermore, despite rapid inactivation by circulating hemoglobin, inhaled nitric oxide exerts effects outside the lung, including blocking platelet aggregation, causing methemoglobinemia, and possibly inducing extrapulmonary vasodilation. The toxicology of inhaled nitric oxide is not completely understood and must be considered in the design of protocols for its safe and effective clinical use.

Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective 1) unconjugated bilirubin uptake and intrahepatic storage, 2) conjugation of glucuronic acid to bilirubin (e.g. Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), 3) bilirubin excretion into bile (Dubin-Johnson syndrome), or 4) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy.

BackgroundPrevious studies have reported decreased birth weight associated with increased air pollutant concentrations during pregnancy. However, it is not clear when during pregnancy increases in air pollution are associated with the largest differences in birth weight.ObjectivesUsing the natural experiment of air pollution declines during the 2008 Beijing Olympics, we evaluated whether having specific months of pregnancy (i.e., 1st…8th) during the 2008 Olympics period was associated with larger birth weights, compared with pregnancies during the same dates in 2007 or 2009.MethodsUsing n = 83,672 term births to mothers residing in four urban districts of Beijing, we estimated the difference in birth weight associated with having individual months of pregnancy during the 2008 Olympics (8 August–24 September 2008) compared with the same dates in 2007 and 2009. We also estimated the difference in birth weight associated with interquartile range (IQR) increases in mean ambient particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) concentrations during each pregnancy month.ResultsBabies whose 8th month of gestation occurred during the 2008 Olympics were, on average, 23 g larger (95% CI: 5 g, 40 g) than babies whose 8th month occurred during the same calendar dates in 2007 or 2009. IQR increases in PM2.5 (19.8 μg/m3), CO (0.3 ppm), SO2 (1.8 ppb), and NO2 (13.6 ppb) concentrations during the 8th month of pregnancy were associated with 18 g (95% CI: –32 g, –3 g), 17 g (95% CI: –28 g, –6 g), 23 g (95% CI: –36 g, –10 g), and 34 g (95% CI: –70 g, 3 g) decreases in birth weight, respectively. We did not see significant associations for months 1–7.ConclusionsShort-term decreases in air pollution late in pregnancy in Beijing during the 2008 Summer Olympics, a normally heavily polluted city, were associated with higher birth weight.CitationRich DQ, Liu K, Zhang J, Thurston SW, Stevens TP, Pan Y, Kane C, Weinberger B, Ohman-Strickland P, Woodruff TJ, Duan X, Assibey-Mensah V, Zhang J. 2015. Differences in birth weight associated with the 2008 Beijing Olympics air pollution reduction: results from a natural experiment. Environ Health Perspect 123:880–887; http://dx.doi.org/10.1289/ehp.1408795

Sulfur mustard (SM) is highly toxic to the lung inducing both acute and chronic effects including upper and lower obstructive disease, airway inflammation, and acute respiratory distress syndrome, and with time, tracheobronchial stenosis, bronchitis, and bronchiolitis obliterans. Thus it is essential to identify effective strategies to mitigate the toxicity of SM and related vesicants. Studies in animals and in cell culture models have identified key mechanistic pathways mediating their toxicity, which may be relevant targets for the development of countermeasures. For example, following SM poisoning, DNA damage, apoptosis, and autophagy are observed in the lung, along with increased expression of activated caspases and DNA repair enzymes, biochemical markers of these activities. This is associated with inflammatory cell accumulation in the respiratory tract and increased expression of tumor necrosis factor-α and other pro-inflammatory cytokines, as well as reactive oxygen and nitrogen species. Matrix metalloproteinases are also upregulated in the lung after SM exposure, which are thought to contribute to the detachment of epithelial cells from basement membranes and disruption of the pulmonary epithelial barrier. Findings that production of inflammatory mediators correlates directly with altered lung function suggests that they play a key role in toxicity. In this regard, specific therapeutic interventions currently under investigation include anti-inflammatory agents (e.g., steroids), antioxidants (e.g., tocopherols, melatonin, N-acetylcysteine, nitric oxide synthase inhibitors), protease inhibitors (e.g., doxycycline, aprotinin, ilomastat), surfactant replacement, and bronchodilators. Effective treatments may depend on the extent of lung injury and require a multi-faceted pharmacological approach.