The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis. Such a model could help researchers and clinicians to evaluate therapies, improve the design of prospective studies, monitor practice patterns, counsel individual patients, and determine the best candidates for lung transplantation. The authors used information from the Cystic Fibrosis Foundation Patient Registry (CFFPR), which has collected longitudinal data on approximately 90% of cystic fibrosis patients diagnosed in the United States since 1986. They developed multivariate logistic regression models by using data on 5,820 patients randomly selected from 11,630 in the CFFPR in 1993. Models were tested for goodness of fit and were validated for the remaining 5,810 patients for 1993. The validated 5-year survivorship model included age, forced expiratory volume in 1 second as a percentage of predicted normal, gender, weight-for-age z score, pancreatic sufficiency, diabetes mellitus, Staphylococcus aureus infection, Burkerholderia cepacia infection, and annual number of acute pulmonary exacerbations. The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research.Keywords cystic fibrosis; logistic models; models, theoretical; multivariate analysis; proportional hazards models; survival analysis Cystic fibrosis is an autosomal recessive, multisystem disease leading to significant morbidity and early death. Since the disease was described in 1938 (1,2), treatments for its pancreatic and pulmonary manifestations have improved median survival in the United States from less than 6 months to about 32 years in 1998 (3). Severe pulmonary disease is the primary cause of cystic-fibrosis-related mortality, constituting 76.4 percent of such deaths in 1998 (3). Chronic inflammation and infection of the airways characterize cystic-fibrosis-related (4,5). Malnutrition, in part due to pancreatic insufficiency, was the major feature of the disease according to early reports, and it continues to be a substantial problem (1-3). With improved survival, additional manifestations such as diabetes mellitus have been recognized (6,7).Many studies have considered the survival effect of a variety of clinical and physiologic features of cystic fibrosis such as forced expiratory volume in 1 second as a percentage of predicted normal (FEV 1 %), gender, age, pregnancy, or particular therapies (4-26). We developed a single survivorship model that integrated many characteristics of cystic fibrosis and quantified the relative contribution of each.The current most commonly used survival model of cystic fibrosis was developed in 1992 and is based on FEV 1 % alone or on age, gender, and FEV 1 % (15). Clinicians often use this model to select patients to refer for lung transplantation. The model is relatively simple to use for estimating cystic fibrosis survival, but it has not been validated and does not incorporate clinical features of cystic fib...

Transforming growth factor-beta1 (TGF-beta1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remains unsettled. We studied the consequences of TGF-beta1 stimulation on freshly isolated human pulmonary artery smooth muscle cells (HPASMC). TGF-beta1 initially promoted differentiation, with upregulated expression of smooth muscle contractile proteins. TGF-beta1 also induced expression of Nox4, the only NAD(P)H oxidase membrane homolog found in HPASMC, through a signaling pathway involving Smad 2/3 but not mitogen-activated protein (MAP) kinases. TGF-beta1 likewise increased production of reactive oxygen species (ROS), an effect significantly reduced by the NAD(P)H oxidase flavoprotein inhibitor diphenylene iodonium (DPI) and by Nox4 siRNAs. In the absence of TGF-beta1, Nox4 was present in freshly cultured cells but progressively lost with each passage in culture, paralleling a decrease in ROS production by HPASMC over time. At a later time point (72 h), TGF-beta1 promoted HPASMC proliferation in a manner partially inhibited by Nox4 small interfering RNA and dominant negative Smad 2/3, indicating that TGF-beta1 stimulates HPASMC growth in part by a redox-dependent mechanism mediated through induction of Nox4. HPASMC activation of the MAP kinases ERK1/2 was reduced by the NAD(P)H oxidase inhibitors DPI and 4-(2-aminoethyl)benzenesulfonyl fluoride, suggesting that TGF-beta1 may facilitate proliferation by upregulating Nox4 and ROS production, with transient oxidative inactivation of phosphatases and augmentation of growth signaling cascades. These findings suggest that Nox4 is the relevant Nox homolog in HPASMC. This is the first observation that TGF-beta1 regulates Nox4, with important implications for mechanisms of pulmonary vascular remodeling.

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231tures which suggest pulmonary veno-occlusive disease or pulmonary hemosiderosis. 1,6 Furthermore, most patients with symptomatic PAH are not referred for lung biopsy due to risk of the procedure, unless there P ulmonary capillary hemangiomatosis (PCH) is a rare disease characterized by a proliferation of multiple layers of capillaries that expand alveolar septa and often invade bronchial walls and the pleura. 1 The disorder is slowly progressive and ultimately fatal. A trial of antiangiogenic therapy followed by lung transplantation is often offered to affected individuals. 2,3 Symptoms, including progressive dyspnea, cough, hemoptysis, fatigue, and weight loss, are not specifi c and mimic other forms of pulmonary arterial hypertension (PAH). Echocardiography and cardiac catheterization may suggest PAH or pulmonary veno-occlusive disease, 4,5 and the diagnosis may prove diffi cult because pathologic examination of lung tissue may show feaBackground: Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown. Methods: We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n 5 1) or sporadic (n 5 10) PCH for mutations. Results: Using exome sequencing, we identifi ed compound mutations in eukaryotic translation initiation factor 2 a kinase 4 ( EIF2AK4 ) (formerly known as GCN2 ) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identifi ed two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress. Conclusions: Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases. CHEST 2014; 145(2):231-236Abbreviations: EIF2AK4 5 eukaryotic translation initiation factor 2 a kinase 4; IRB 5 institutional review board; PAH 5 pulmonary arterial hypertension; PCH 5 pulmonary capillary hemangiomatosis

Persistent hypoxia can cause pulmonary arterial hypertension that may be associated with significant remodeling of the pulmonary arteries, including smooth muscle cell proliferation and hypertrophy. We previously demonstrated that the NADPH oxidase homolog NOX4 mediates human pulmonary artery smooth muscle cell (HPASMC) proliferation by transforming growth factor-beta1 (TGF-beta1). We now show that hypoxia increases HPASMC proliferation in vitro, accompanied by increased reactive oxygen species generation and NOX4 gene expression, and is inhibited by antioxidants, the flavoenzyme inhibitor diphenyleneiodonium (DPI), and NOX4 gene silencing. HPASMC proliferation and NOX4 expression are also observed when media from hypoxic HPASMC are added to HPASMC grown in normoxic conditions, suggesting autocrine stimulation. TGF-beta1 and insulin-like growth factor binding protein-3 (IGFBP-3) are both increased in the media of hypoxic HPASMC, and increased IGFBP-3 gene expression is noted in hypoxic HPASMC. Treatment with anti-TGF-beta1 antibody attenuates NOX4 and IGFBP-3 gene expression, accumulation of IGFBP-3 protein in media, and proliferation. Inhibition of IGFBP-3 expression with small interfering RNA (siRNA) decreases NOX4 gene expression and hypoxic proliferation. Conversely, NOX4 silencing does not decrease hypoxic IGFBP-3 gene expression or secreted protein. Smad inhibition does not but the phosphatidylinositol 3-kinase (PI3K) signaling pathway inhibitor LY-294002 does inhibit NOX4 and IGFBP-3 gene expression, IGFBP-3 secretion, and cellular proliferation resulting from hypoxia. Immunoblots from hypoxic HPASMC reveal increased TGF-beta1-mediated phosphorylation of the serine/threonine kinase (Akt), consistent with hypoxia-induced activation of PI3K/Akt signaling pathways to promote proliferation. We conclude that hypoxic HPASMC produce TGF-beta1 that acts in an autocrine fashion to induce IGFBP-3 through PI3K/Akt. IGFBP-3 increases NOX4 gene expression, resulting in HPASMC proliferation. These observations add to our understanding hypoxic pulmonary vascular remodeling.