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Cigarette smoking (CS) and genetic susceptibility determine the risk for development, progression, and severity of chronic obstructive pulmonary diseases (COPD). We posited that an incidental balanced reciprocal chromosomal translocation was linked to a patient's risk of severe COPD. We determined that 46,XX,t(1;4)(p13.1;q34.3) caused a breakpoint in the immunoglobulin superfamily member 3 (IGSF3) gene, with markedly decreased expression. Examination of COPDGene cohort identified 14 IGSF3 SNPs, of which rs1414272 and rs12066192 were directly and rs6703791 inversely associated with COPD severity, including COPD exacerbations. We confirmed that IGSF3 is a tetraspanin-interacting protein that colocalized with CD9 and integrin B1 in tetraspanin-enriched domains. IGSF3-deficient patient-derived lymphoblastoids exhibited multiple alterations in gene expression, especially in the unfolded protein response and ceramide pathways. IGSF3-deficient lymphoblastoids had high ceramide and sphingosine-1 phosphate but low glycosphingolipids and ganglioside levels, and they were less apoptotic and more adherent, with marked changes in multiple TNFRSF molecules. Similarly, IGSF3 knockdown increased ceramide in lung structural cells, rendering them more adherent, with impaired wound repair and weakened barrier function. These findings suggest that, by maintaining sphingolipid and membrane receptor homeostasis, IGSF3 is required for cell mobility-mediated lung injury repair. IGSF3 deficiency may increase susceptibility to CS-induced lung injury in COPD.

Elevated levels of reactive oxygen species and intracellular Ca2+ play a key role in endothelial barrier dysfunction in acute lung injury. We previously showed that H2O2-induced increases in intracellular calcium concentrations ([Ca2+]i) in lung microvascular endothelial cells (LMVECs) involve the membrane Ca2+ channel, transient receptor potential vanilloid-4 (TRPV4) and that inhibiting this channel attenuated H2O2-induced barrier disruption in vitro. We also showed that phosphorylation of TRPV4 by the Src family kinase, Fyn, contributes to H2O2-induced Ca2+ influx in LMVEC. In endothelial cells, Fyn is tethered to the cell membrane by CD36, a fatty acid transporter. In this study, we assessed the effect of genetic loss or pharmacological inhibition of CD36 on Ca2+ responses to H2O2. H2O2-induced Ca2+ influx was attenuated in LMVEC isolated from mice lacking CD36 ( CD36−/−). TRPV4 expression and function was unchanged in LMVEC isolated from wild-type (WT) and CD36−/− mice, as well as mice with deficiency for Fyn ( Fyn−/−). TRPV4 immunoprecipitated with Fyn, but this interaction was decreased in CD36−/− LMVEC. The amount of phosphorylated TRPV4 was decreased in LMVEC from CD36−/− mice compared with WT controls. Loss of CD36 altered subcellular localization of Fyn, while inhibition of CD36 fatty acid transport with succinimidyl oleate did not attenuate H2O2-induced Ca2+ influx. Lastly, we found that CD36−/− mice were protected from ischemia-reperfusion injury in vivo. In conclusion, our data suggest that CD36 plays an important role in H2O2-mediated lung injury and that the mechanism may involve CD36-dependent scaffolding of Fyn to the cell membrane to facilitate TRPV4 phosphorylation.

Purpose The objective of this study was to assess whether earlier antibiotic administration in patients with systemic inflammatory response syndrome (SIRS) and evidence of organ dysfunction identified through electronic alerts improves patient mortality. Methods This is a retrospective observational cohort study of adult patients admitted across 5 acute-care hospitals. Mortality, Premier CareScienceTM Analytics Expected Mortality Score, and clinical and demographic variables were obtained through the electronic medical record and Premier (Premier Healthcare Solutions, Inc, Charlotte NC) reports. Patients with 2 SIRS criteria and organ dysfunction were identified through an automated alert. Univariate and multivariate logistic regression was performed. Results Of those with SIRS and organ dysfunction, 8146 patients were identified through the electronic Best Practice Alert (BPA). Overall 30-day mortality rate was 8.7%. There was no significant association between time to antibiotic administration from BPA alert and mortality (P = 0.21) after adjusting for factors that could influence mortality, including age, heart rate, blood pressure, plasma lactate levels, creatinine, bilirubin levels, and the CareScienceTM Predicted Mortality Risk Score. Female gender (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.06-1.63) and facility were also independently associated with mortality. Conclusion The use of alerts in the electronic medical record may misclassify patients with SIRS as having sepsis. Time to antibiotic administration in patients meeting SIRS criteria and evidence of end-organ dysfunction through BPA alerts did not affect 30-day mortality rates across a health system. Patient severity of illness, gender, and facility also independently predicted mortality. There were higher rates of antibiotic use and Clostridioides difficile infection in patients with BPA alerts.

In acute respiratory distress syndrome, both reactive oxygen species (ROS) and increased intracellular calcium ([Ca2+]i) are thought to play important roles in promoting endothelial paracellular permeability, but the mechanisms linking ROS and [Ca2+]i in microvascular endothelial cells are not known. In this study, we assessed the effect of hydrogen peroxide (H2O2) on [Ca2+]i in mouse and human lung microvascular endothelial cells (MLMVEC and HLMVEC, respectively). We found that in both MLMVECs and HLMVECs, exogenously applied H2O2 increased [Ca2+]i through Ca2+ influx and that pharmacologic inhibition of the calcium channel transient receptor potential vanilloid 4 (TRPV4) attenuated the H2O2-induced Ca2+ influx. Additionally, knockdown of TRPV4 in HLMVEC also attenuated calcium influx following H2O2 challenge. Administration of H2O2 or TRPV4 agonists decreased transmembrane electrical resistance (TER), suggesting increased barrier permeability. To explore the regulatory mechanisms underlying TRPV4 activation by ROS, we examined H2O2-induced Ca2+ influx in MLMVECs and HLMVECs with either genetic deletion, silencing, or pharmacologic inhibition of Fyn, a Src family kinase. In both MLMVECs derived from mice deficient for Fyn and HLMVECs treated with either siRNA targeted to Fyn or the Src family kinase inhibitor SU-6656 for 24 or 48 h, the H2O2-induced Ca2+ influx was attenuated. Treatment with SU-6656 decreased the levels of phosphorylated, but not total, TRPV4 protein and had no effect on TRPV4 response to the external agonist, GSK1016790A. In conclusion, our data suggest that application of exogenous H2O2 increases [Ca2+]i and decreases TER in microvascular endothelial cells via activation of TRPV4 through a mechanism that requires the Src kinase Fyn.

Background European trials using procalcitonin (PCT)-guided antibiotic therapy for patients with lower respiratory tract infections (LRTI) have resulted in significant reductions in antibiotic use without increasing adverse outcomes. Few prospective studies have examined PCT-guided antibiotic therapy for LRTI in the United States. Our objective was to examine whether an PCT algorithm compared with standard practice would reduce antibiotic exposure in patients with LRTI [pneumonia and acute exacerbations of chronic obstructive pulmonary disease (AECOPD)] in an American urban academic hospital. Methods From April 17, 2017 until November 1, 2017, consecutive patients admitted to a medicine service were enrolled in the PCT intervention if they were receiving antibiotics for LRTI and gave consent. Providers were encouraged to discontinue antibiotics using a PCT algorithm with predefined cutoffs. Serum PCT was measured in the hospital laboratory once daily. Results and recommendations were communicated to providers by study team and in the medical record. Control patients were selected by reviewing charts for patients admitted to a medicine service for LRTI from December 1, 2016 to April 16, 2017. The primary endpoint was median antibiotic duration. Overall adverse outcomes at 30 days comprised death, transfer to an intensive care unit, antibiotic side effects, Clostridium difficile infection, disease- specific complications, and new antibiotic prescription for LRTI after discharge. Results 174 patients were enrolled in the intervention group and 200 patients in the control group. Intervention group providers complied with the PCT algorithm in 75% of encounters. The rate of overall adverse outcomes was similar in PCT and control groups (21.8% vs. 23.5%; difference, –0.02; 95% CI, –0.10 to 0.07). PCT-guided therapy reduced the median antibiotic duration for pneumonia from 7 days to 6 (P = 0.05), and AECOPD from 4 days to 3 (P = 0.01). Noncompliance with the PCT algorithm resulted in 260 excess antibiotic days in 44 patients. Conclusion In our center, 75% adherence to a PCT-guided algorithm safely reduced the duration of antibiotics for treating LRTI. Incentivizing providers to comply with PCT-guided algorithms could lead to further reductions in antibiotic use. Disclosures J. Townsend, BRAHMS: Grant Investigator, Research grant.

We present a case of onset of severe asthma in a 59-year-old patient who worked in an aerospace plant. He was noted to have wheezing on exam and obstruction on PFTs. Review of his occupational history revealed exposure to lipophilic industrial compounds. We outline the radiographic and histologic findings that were found in the patient, and discuss occupational asthma due to inhalation of lipophilic compounds.

Clinicians frequently see the “right middle lobe” referred to in radiology reports, textbooks, and medical journals. Yet, there is no “left” middle lobe to distinguish it from, save a rare patient with Kartagener syndrome. We do not refer to the lingula as the “left” lingula. “Right” adds nothing to our understanding of the anatomic position of the lobe. So “right” is redundant when talking about the middle lobe. Yet, PubMed has 5,266 right middle lobe references, and a Google Scholars search found 22,900 publications used the phrase in the past 161 years. Th at is the equivalent of the length of two and one-half football fi elds worth of wasted words in just a Google search, nevermind those found in radiology reports, textbooks, or Index Medicus references (in Calibri font size 12, “right” 5 1 cm 3 22,900 search results 5 228.99 m).