Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPE(BD)). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPE(BD) decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HV(T)) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HV(T) (P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HV(T) (P < 0.05). BAL fluid from rats exposed to 20 min of HV(T) increased nitric oxide synthase activity nearly threefold in naïve primary alveolar macrophages (P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naïve macrophages (P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.

Background: Clinical studies have shown that injurious mechanical ventilation is associated with increased airspace and plasma levels of interleukin-1b (IL-1b); however, the potential therapeutic value of IL-1 inhibition in acute lung injury has not been thoroughly investigated. A study was undertaken to determine if IL-1 signalling is a necessary early event in the pathogenesis of experimental ventilator-induced lung injury. Methods: Mice deficient in IL-1 receptor type 1 (IL1R1) and rats treated with IL-1 receptor antagonist (IL-1Ra) were mechanically ventilated with high tidal volume (30 ml/kg) and the effect of IL-1 signalling blockade on the severity of lung injury was determined. Results: Permeability, as measured by radiolabelled albumin flux, was significantly lower in IL1R1 null mice than in wild-type mice during injurious ventilation (p,0.05). IL-1Ra significantly decreased protein permeability and pulmonary oedema in rats during injurious ventilation and also decreased airspace and plasma levels of the chemokine CXCL1 and airspace neutrophils. IL-1Ra decreased expression of NOS2 and ICAM-1 mRNA in whole lung. Bronchoalveolar lavage fluid levels of RTI40, a marker of type I cell injury, were 2.5 times lower following IL-1Ra treatment (p,0.05). In isolated type II pneumocytes, IL-1b reduced electrical resistance and increased transepithelial permeability. Conclusions: IL-1 contributes to alveolar barrier dysfunction in VILI by promoting lung neutrophil recruitment and by increasing epithelial injury and permeability. Because preserved alveolar barrier function is associated with better outcomes in patients with acute lung injury, these data support further testing of IL-1Ra for the treatment of acute lung injury.Acute lung injury, including the acute respiratory distress syndrome (ARDS), is a common cause of respiratory failure associated with 40% mortality.

In this analysis, sigmoid colon cancers were observed to have earlier stage, lower tumor grade, and independently decreased colorectal cancer-specific mortality compared with proximal tumors.

IMPORTANCE Transient elevations of blood pressure (BP) are common in hospitalized older adults and frequently lead practitioners to prescribe more intensive antihypertensive regimens at hospital discharge than the patients were using before hospitalization.OBJECTIVE To investigate the association between intensification of antihypertensive regimens at hospital discharge and clinical outcomes after discharge. DESIGN, SETTING, AND PARTICIPANTSIn this retrospective cohort study, patients 65 years and older with hypertension who were hospitalized in Veterans Health Administration national health system facilities from January 1, 2011, to December 31, 2013, for common noncardiac conditions were studied. Data analysis was performed from October 1, 2018, to March 10, 2019.EXPOSURES Discharge with antihypertensive intensification, defined as receiving a prescription at hospital discharge for a new or higher-dose antihypertensive than was being used before hospitalization. Propensity scores were used to construct a matched-pairs cohort of patients who did and did not receive antihypertensive intensifications at hospital discharge. MAIN OUTCOMES AND MEASURESThe primary outcomes of hospital readmission, serious adverse events, and cardiovascular events were assessed by competing risk analysis. The secondary outcome was the change in systolic BP within 1 year of hospital discharge. RESULTSThe propensity-matched cohort included 4056 hospitalized older adults with hypertension (mean [SD] age, 77 [8] years; 3961 men [97.7%]), equally split between those who did vs did not receive antihypertensive intensifications at hospital discharge. Groups were well matched on all baseline covariates (all standardized mean differences <0.1). Within 30 days, patients receiving intensifications had a higher risk of readmission (hazard ratio [HR], 1.23; 95% CI, 1.07-1.42; number needed to harm [NNH], 27; 95% CI, 16-76) and serious adverse events (HR, 1.41; 95% CI, 1. NNH, 63; 95% CI,. At 1 year, no differences were found in cardiovascular events (HR, 1.18; 95% CI, 0.99-1.40) or change in systolic BP among those who did vs did not receive intensifications (mean BP, 134.7 vs 134.4; difference-in-differences estimate, 0.6 mm Hg; 95% CI, −2.4 to 3.7 mm Hg).CONCLUSIONS AND RELEVANCE Among older adults hospitalized for noncardiac conditions, prescription of intensified antihypertensives at discharge was not associated with reduced cardiac events or improved BP control within 1 year but was associated with an increased risk of readmission and serious adverse events within 30 days.