Hypercapnia Alters Alveolar Epithelial Repair by a pH-Dependent and Adenylate Cyclase-Mediated Mechanism.

Lung cell injury and repair is a hallmark of the acute respiratory distress syndrome (ARDS). Lung protective mechanical ventilation strategies in these patients may lead to hypercapnia (HC). Although HC has been explored in the clinical context of ARDS, its effect upon alveolar epithelial cell (AEC) wounding and repair remains poorly understood. We have previously reported that HC alters the likelihood of AEC repair by a pH-sensitive but otherwise unknown mechanism. Adenylate cyclase (AC) is an attractive candidate as a putative AEC CO2 sensor and effector as it is bicarbonate sensitive and controls key mediators of AEC repair. The effect of HC on AC activity and plasma membrane (PM) wound repair was measured in AEC type 1 exposed to normocapnia (NC, 40 Torr) or HC (80 Torr), ± tromethamine (THAM) or sodium bicarbonate (HCO3) ± AC probes in a micropuncture model of AEC injury relevant to ARDS. Intracellular pH and AC activity were measured and correlated with repair. HC decreased intracellular pH 0.56, cAMP by 37%, and absolute PM repair rate by 26%. Buffering or pharmacologic manipulation of AC reduced or reversed the effects of HC on AC activity (THAM 103%, HCO3 113% of NC cAMP, ns; Forskolin 168%, p < 0.05) and PM repair (THAM 87%, HCO3 108% of NC likelihood to repair, ns; Forskolin 160%, p < 0.01). These findings suggest AC to be a putative AEC CO2 sensor and modulator of AEC repair, and may have implications for future pharmacologic targeting of downstream messengers of the AC-cAMP axis in experimental models of ARDS.

Insulin resistance, oxidative stress, and podocyte injury: role of rosuvastatin modulation of filtration barrier injury.

BACKGROUND/AIM: There is an emerging relationship between insulin resistance/hyperinsulinemia, oxidative stress, and glomerular injury manifesting as albuminuria. HMG-CoA reductase inhibitors (statins) have been shown to reduce oxidative stress in the vasculature as well as albuminuria in animal models and in human studies. The glomerular filtration barrier is emerging as a critical determinant of albumin filtration. We investigated the effects of insulin resistance and rosuvastatin or placebo on the glomerular filtration barrier. METHOD: Young Zucker obese and Zucker lean rats (6-7 weeks old) were treated with the HMG-CoA reductase inhibitor rosuvastatin (10 mg/kg/day) or placebo for 21 days. RESULTS: In the Zucker obese rats, homeostasis model assessment-insulin resistance index, oxidative markers (NADPH oxidase activity, reactive oxygen species, and urine isoprostane formation), podocyte foot process effacement, and albuminuria were increased as compared with Zucker lean controls, independent of increases in systolic blood pressure. Albuminuria correlated with podocyte foot process effacement (r(2) = 0.61) and insulin level (r(2) = 0.69). Rosuvastatin treatment improved albuminuria, filtration barrier indices, and oxidative stress via copper/zinc superoxide dismutase. CONCLUSIONS: These data indicate that hyperinsulinemia together with insulin resistance is associated with podocyte injury and albuminuria independent of the systolic blood pressure. Further, rosuvastatin modulates filtration barrier injury and albuminuria and improves oxidative stress measures via copper/zinc superoxide dismutase.

Patients With Fibrotic Interstitial Lung Disease Hospitalized for Acute Respiratory Worsening: A Large Cohort Analysis.

BACKGROUND: Acute respiratory worsening (ARW) requiring hospitalization in patients with fibrotic interstitial lung disease (f-ILD) is common. Little is known about the frequency and implications of ARW in IPF and non-IPF ILD patients hospitalized for acute exacerbation (AE) vs known causes of ARW. METHODS: All consecutive patients with f-ILD hospitalized with ARW at our institution from 2000 to 2014 were reviewed. ARW was defined as any worsening of respiratory symptoms with new or worsened hypoxemia or hypercapnia within 30 days of admission. Suspected AE was defined using modified 2007 American Thoracic Society/European Respiratory Society criteria. Known causes of ARW were reviewed and collated along with in-hospital and all-cause mortality postdischarge. RESULTS: A total of 220 patients (100 with IPF and 120 non-IPF) composed 311 admissions for ARW. Suspected AE (SAE) comprised 52% of ARW admissions, followed by infection (20%), and subacute progression of disease (15%). In-hospital mortality was similar in patients with IPF vs patients without (55 vs 45%, P = .18), but worse in suspected AE admission types (OR, 3.1 [1.9-5.14]). One-year survival after last ARW admission for the whole cohort was 22%, despite only 27% of patients presenting with baseline oxygen requirement at admission and a mean admission Charlson Comorbidity Index score of 5.4 (expected 1-year survival, 89%). Survival after discharge was similar between SAE and secondary ARW admission types in both IPF and non-IPF patients. CONCLUSIONS: Among patients with f-ILD, hospitalization for ARW appears associated with significant in-hospital and postdischarge mortality regardless of underlying fibrotic lung disease or non-AE cause of acute respiratory decline.

Morbidity and mortality characteristics of morbidly obese patients admitted to hospital and intensive care units.

BACKGROUND: The purpose of this study is to evaluate the outcomes of hospitalized morbidly obese inpatients. METHODS: In this retrospective cohort study, we reviewed the records of all adult morbidly obese patients (defined as body mass index [BM]) >40 kg/m(2) upon admission) admitted to tertiary university hospital from 2000 to 2008. Primary outcome was hospital mortality. Secondary outcomes were hospital and intensive care unit (ICU) length of stay (LOS), need for and duration of mechanical ventilation (MV), and tracheostomy rates. We divided patients into quartiles based on their admission BMI. Baseline characteristics and outcomes were reported for each quartile. RESULTS: Over the 8-year period, we reviewed 897 admissions for 545 patients. The median number of admissions was 1 per patient (mean, 2.44 ± 2.9), with a range of 1 to 20. A total of 40.9% had more than one admission. Morbidly obese patients were more likely to be admitted to a medical service. Higher BMI quartiles had higher rates of ICU admission, MV, and rate of tracheostomy. Although the higher BMI quartiles had longer hospital LOS, hospital mortality did not significantly differ. CONCLUSIONS: As BMI increases, utilization of medical resources also increases such as ICU admission, MV, longer hospital LOS, and tracheostomy. Although overall BMI interquartile mortality rates do not differ significantly in our study, utilization of valuable and costly hospital resources is a major challenge facing health care delivery. Our findings indicate the need for increased efforts and novel strategies for treatment, prevention, and resource allocation to deal with this emerging challenge.

Respiratory syncytial virus infections in the adult asthmatic--mechanisms of host susceptibility and viral subversion.

Respiratory syncytial virus (RSV), a single-stranded RNA virus of the Paramyxoviridae family, is a major cause of bronchiolitis in infants and is also conjectured to be an early-life influence on the development of asthma. Although the data supporting a role for RSV in bronchiolitis in children are robust and evidence to support its role in juvenile asthmatics exists, RSV's role in asthma pathogenesis in adults is not as clearly defined. The authors review the literature to further elucidate RSV's impact on adult asthmatics, including its importance as a cause of asthma exacerbations. They examine the morbidity associated with RSV infection and how the immune response may differ between adult asthmatics and nonasthmatics. They review the responses by specific cell types from adults with asthma that are stimulated by RSV. They also consider the role of early-life exposure to RSV and its contribution to asthma in adults. Lastly, they review the mechanisms by which RSV evades normal host immune responses and subverts these responses to its benefit.