Acute respiratory distress syndrome (ARDS) is a severe clinical condition marked by acute respiratory failure and dysregulated inflammation. Pulmonary vascular endothelial cells (PVEC) function as an important pro-inflammatory source in ARDS, suggesting that modulation of inflammatory events at the endothelial level may have therapeutic benefit. Dipeptidyl peptidase-4 (DPP4) inhibitors, widely used for the treatment of diabetes mellitus, have been reported to have possible anti-inflammatory effects. However, the potential anti-inflammatory effects of DPP4 inhibition on PVEC function and ARDS pathophysiology are unknown. Therefore, we evaluated the effects of sitagliptin, a DPP4 inhibitor in wide clinical use, on LPS-induced lung injury in mice and in human lung endothelial cells (EC) in vitro. In vivo, sitagliptin reduced serum DPP4 activity, BAL protein concentration, cell number and pro-inflammatory cytokine levels, after LPS, and alleviated histological findings of lung injury. LPS decreased the expression levels of CD26/DPP4 on pulmonary epithelial cells and PVEC isolated from mouse lungs, and the effect was partially reversed by sitagliptin. In vitro, human lung microvascular EC (HLMVEC) expressed higher levels of CD26/DPP4 than human pulmonary arterial EC. LPS induced release of TNFα, IL-6, and IL-8 by HLMVEC that was inhibited by sitagliptin. LPS promoted proliferation of HLMVEC, and sitagliptin suppressed this response. However, sitagliptin failed to reverse LPS-induced permeability in cultured EC or lung epithelial cells in vitro. In summary, sitagliptin attenuates LPS-induced lung injury in mice and exerts anti-inflammatory effects on HLMVEC. These novel observations indicate DPP4 inhibitors may have potential as therapeutic drugs for ARDS.

The pulmonary endothelial cell forms a critical semi-permeable barrier between the vascular and interstitial space. As part of the blood-gas barrier in the lung, the endothelium plays a key role in normal physiologic function and pathologic disease. Changes in endothelial cell shape, defined by its plasma membrane, determine barrier integrity. A number of key cytoskeletal regulatory and effector proteins including non-muscle myosin light chain kinase, cortactin, and Arp 2/3 mediate actin rearrangements to form cortical and membrane associated structures in response to barrier enhancing stimuli. These actin formations support and interact with junctional complexes and exert forces to protrude the lipid membrane to and close gaps between individual cells. The current knowledge of these cytoskeletal processes and regulatory proteins are the subject of this review. In addition, we explore novel advancements in cellular imaging that are poised to shed light on the complex nature of pulmonary endothelial permeability.

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The secretory phospholipase A 2 (sPLA 2 ) group of secreted enzymes hydrolyze phospholipids and lead to the production of multiple biologically active lipid mediators. sPLA 2 s and their products (e.g., eicosanoids) play a significant role in the pathophysiology of various inflammatory diseases, including life-threatening lung disorders such as acute lung injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS). The ALI/ARDS spectrum of severe inflammatory conditions is caused by direct (such as bacterial or viral pneumonia) or indirect insults (sepsis) that are associated with high morbidity and mortality. Several sPLA 2 isoforms are upregulated in patients with ARDS as well as in multiple ALI preclinical models, and individual sPLA 2 s exert unique roles in regulating ALI pathophysiology. This brief review will summarize the contributions of specific sPLA 2 isoforms as markers and mediators in ALI, supporting a potential therapeutic role for targeting them in ARDS.

Purpose In acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between arterial and end-tidal CO2 (arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS. Methods We performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (N = 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (N = 302) as a validation cohort. Results The ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (P = 0.047). In a separate analysis, the modified Enghoff equation ((PaCO2–PETCO2)/PaCO2) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (P = 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results. Conclusion Arterial to end-tidal CO2 (ETCO2) difference is an independent predictor of mortality in patients with ARDS.