Impact of Age and Sex on Outcomes and Hospital Cost of Acute Asthma in the United States, 2011-2012

Background Worldwide, asthma is a leading cause of morbidity, mortality and economic burden, with significant gender and racial disparities. However, little attention has been given to the independent role of age on lifetime asthma severity and hospitalization. We aimed to assess the effect of age, gender, race and ethnicity on indicators of asthma severity including asthma related hospitalization, mortality, hospital cost, and the rate of respiratory failure. Methods We analyzed the 2011 and 2012 Healthcare Cost and Utilization Project- National Inpatient Sample (NIS). We validated and extended those results using the National Heart, Lung, and Blood Institute-Severe Asthma Research Program (SARP; 2002-2011) database. Severe asthma was prospectively defined using the stringent American Thoracic Society (ATS) definition. Results Hospitalization for asthma was reported in 372,685 encounters in 2012 and 368,528 in 2011. The yearly aggregate cost exceeded $2 billion. There were distinct bimodal distributions for hospitalization age, with an initial peak at 5 years and a second at 50 years. Likewise, this bimodal age distribution of patients with severe asthma was identified using SARP. Males comprised the majority of individuals in the first peak, but women in the second. Aggregate hospital cost mirrored the bimodal peak distribution. The probability of respiratory failure increased with age until the age of 60, after which it continued to increase in men, but not in women. Conclusions Severe asthma is primarily a disease of young boys and middle age women. Greater understanding of the biology of lung aging and influence of sex hormones will allow us to plan for targeted interventions during these times in order to reduce the personal and societal burdens of asthma

Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells

Exhaled nitric oxide (eNO) is decreased by cigarette smoking. The hypothesis that oxides of nitrogen (NO(X)) in cigarette smoke solution (CSS) may exert a negative feedback mechanism upon NO release from epithelial (AEC, A549, and NHTBE) and basophilic cells (RBL-2H3) was tested in vitro. CSS inhibited both NO production and degranulation (measured as release of beta-hexosaminidase) in a dose-dependent manner from RBL-2H3 cells. Inhibition of NO production by CSS in AEC, A549, and NHTBE cells was also dose-dependent. In addition, CSS decreased expression of NOS mRNA and protein expression. The addition of NO inhibitors and scavengers did not, however, reverse the effects of CSS, nor did a NO donor (SNP) or nicotine mimic CSS. N-acetyl-cysteine, partially reversed the inhibition of beta-hexosaminidase release suggesting CSS may act via oxidative free radicals. Thus, some of the inhibitory effects of CSS appear to be via oxidative free radicals rather than a NO(X )-related negative feedback

Disparate oxidant gene expression of airway epithelium compared to alveolar macrophages in smokers

<p>Abstract</p> <p>Background</p> <p>The small airway epithelium and alveolar macrophages are exposed to oxidants in cigarette smoke leading to epithelial dysfunction and macrophage activation. In this context, we asked: what is the transcriptome of oxidant-related genes in small airway epithelium and alveolar macrophages, and does their response differ substantially to inhaled cigarette smoke?</p> <p>Methods</p> <p>Using microarray analysis, with TaqMan RT-PCR confirmation, we assessed oxidant-related gene expression in small airway epithelium and alveolar macrophages from the same healthy nonsmoker and smoker individuals.</p> <p>Results</p> <p>Of 155 genes surveyed, 87 (56%) were expressed in both cell populations in nonsmokers, with higher expression in alveolar macrophages (43%) compared to airway epithelium (24%). In smokers, there were 15 genes (10%) up-regulated and 7 genes (5%) down-regulated in airway epithelium, but only 3 (2%) up-regulated and 2 (1%) down-regulated in alveolar macrophages. Pathway analysis of airway epithelium showed oxidant pathways dominated, but in alveolar macrophages immune pathways dominated.</p> <p>Conclusion</p> <p>Thus, the response of different cell-types with an identical genome exposed to the same stress of smoking is different; responses of alveolar macrophages are more subdued than those of airway epithelium. These findings are consistent with the observation that, while the small airway epithelium is vulnerable, alveolar macrophages are not "diseased" in response to smoking.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov ID: NCT00224185 and NCT00224198</p

Effects of controlled diesel exhaust exposure on apoptosis and proliferation markers in bronchial epithelium – an in vivo bronchoscopy study on asthmatics, rhinitics and healthy subjects

BackgroundEpidemiological evidence demonstrates that exposure to traffic-derived pollution worsens respiratory symptoms in asthmatics, but controlled human exposure studies have failed to provide a mechanism for this effect. Here we investigated whether diesel exhaust (DE) would induce apoptosis or proliferation in the bronchial epithelium in vivo and thus contribute to respiratory symptoms.MethodsModerate (n?=?16) and mild (n?=?16) asthmatics, atopic non-asthmatic controls (rhinitics) (n?=?13) and healthy controls (n?=?21) were exposed to filtered air or DE (100 ?g/m 3 ) for 2 h, on two separate occasions. Bronchial biopsies were taken 18 h post-exposure and immunohistochemically analysed for pro-apoptotic and anti-apoptotic proteins (Bad, Bak, p85 PARP, Fas, Bcl-2) and a marker of proliferation (Ki67). Positive staining was assessed within the epithelium using computerized image analysis.ResultsNo evidence of epithelial apoptosis or proliferation was observed in healthy, allergic or asthmatic airways following DE challenge.ConclusionIn the present study, we investigated whether DE exposure would affect markers of proliferation and apoptosis in the bronchial epithelium of asthmatics, rhinitics and healthy controls, providing a mechanistic basis for the reported increased airway sensitivity in asthmatics to air pollutants. In this first in vivo exposure investigation, we found no evidence of diesel exhaust-induced effects on these processes in the subject groups investigated

Complement C3 Deficiency Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension in Mice

Background: Evidence suggests a role of both innate and adaptive immunity in the development of pulmonary arterial hypertension. The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension. Methodology/Principal Findings: Immunofluorescent staining revealed significant C3d deposition in lung sections from IPAH patients and C57Bl6/J wild-type mice exposed to three weeks of chronic hypoxia to induce pulmonary hypertension. Right ventricular systolic pressure and right ventricular hypertrophy were increased in hypoxic vs. normoxic wild-type mice, which were attenuated in C3-/- hypoxic mice. Likewise, pulmonary vascular remodeling was attenuated in the C3-/- mice compared to wild-type mice as determined by the number of muscularized peripheral arterioles and morphometric analysis of vessel wall thickness. The loss of C3 attenuated the increase in interleukin-6 and intracellular adhesion molecule-1 expression in response to chronic hypoxia, but not endothelin-1 levels. In wild-type mice, but not C3-/- mice, chronic hypoxia led to platelet activation as assessed by bleeding time, and flow cytometry of platelets to determine cell surface P-selectin expression. In addition, tissue factor expression and fibrin deposition were increased in the lungs of WT mice in response to chronic hypoxia. These pro-thrombotic effects of hypoxia were abrogated in C3-/- mice. Conclusions: Herein, we provide compelling genetic evidence that the complement system plays a pathophysiologic role in the development of PAH in mice, promoting pulmonary vascular remodeling and a pro-thrombotic phenotype. In addition we demonstrate C3d deposition in IPAH patients suggesting that complement activation plays a role in the development of PAH in humans. © 2011 Bauer et al

Hyaluronan Mediates Contractility In Pulmonary Artery Smooth Muscle Cells In Idiopathic Pulmonary Arterial Hypertension

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease and the pathobiology is typified by cell proliferation, inflammation and vascular remodeling. Hyaluronan (HA), a large glycosaminoglycan found in the extracellular matrix, has major roles in lung and vascular biology and disease. We have previously demonstrated that pulmonary artery smooth muscle cells (PASMCs) from IPAH lungs spontaneously produce high levels of HA. We hypothesized that HA produced by PASMCs contributes to their contractility.METHODS: PASMCs were obtained from explanted lungs. Human PASMC were isolated from elastic pulmonary arteries (>500-um diameter) dissected from lungs obtained at explantation during lung transplant. The collagen gel contraction assay was used as a measure of cell contractility. Circular agarose molds were prepared using 10-mm diameter cloning cylinders and 3% agarose solution. A solution of rat-tail collagen was mixed with PASMCs (3 x 105/ml) suspended in SmGM supplemented with 10% FBS and antibiotics, and the PASMC-collagen mixture was pipetted into circular agarose molds of 24-well tissue culture plates. Gels were polymerized at 37°C for 1 h, overlaid with 1 ml of conditioned media, gently detached from the sides and bottom of the mold with a spatula, and allowed to contract as suspended gels for 16 h. In some experiments cells were cultured with addition of hyaluronidase. The gels were scanned and the gel area was measured using Image J software and expressed as percentage of gel area on the image.RESULTS: Collagen gel contraction assay showed that IPAH PASMCs contract a collagen gel to a greater extent compared to control PASMCs [Percentage of gel area on the image (mean±SD): IPAH 31±3, Control; 46±5 p<0.0001]. Treatment of IPAH PASMCs with hyaluronidase resulted in a contraction response that is more similar to control cells [Percentage of gel area on the image (mean±SD): IPAH PASMC 32±1.2, IPAH PASMC with Hyaluronidase; 40±1.3 p<0.01]. Treatment of control PASMC with hyaluronidase did not change their contraction properties significantly [Percentage of gel area on the image (mean±SD): Control PASMC 57±4, Control PASMC with Hyaluronidase; 53±2 p=0.37]CONCLUSIONS: HA produced by PASMC has important roles in PASMC contraction