Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α–responsive, heparan sulfate–specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.

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Our understanding of the pathobiology of severe pulmonary hypertension, usually a fatal disease, has been hampered by the lack of information of its natural history. We have demonstrated that, in human severe pulmonary hypertension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) are involved in proper maintenance, differentiation, and function of endothelial cells. We demonstrate here that VEGFR-2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells. Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416-treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z-Asp-CH2-DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.interstitial lung disease ͉ liver fibrosis ͉ telomerase ͉ aplastic anemia ͉ dyskeratosis congenita

Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a critical mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the VEGF receptors in both rats and mice. Emphysema was reproduced with intra-tracheal instillation of ceramide in naïve mice. A feed-forward mechanism of ceramide synthesis due secretory acid sphingomyelinase was supported by the neutralizing effects of ceramide-specific antibody in mice and by sphingomyelinase-deficient fibroblasts. Stimulation of sphingosine-1-phosphate signaling prevented lung apoptosis, implicating that ceramide to sphingosine-1-phosphate balance is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in patients with smoking-induced emphysema position ceramide upregulation as a critical pathogenetic element and a promising target in this disease lacking effective therapies.