Francis X. McCormack

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

BACKGROUND Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling. METHODS We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed. RESULTS Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections. CONCLUSIONS Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Efficacy and safety of sirolimus in lymphangioleiomyomatosis

BACKGROUND Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. METHODS We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). RESULTS During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. CONCLUSIONS In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung

The data presented here suggest that SP-A and SP-D perform distinct, as well as complementary, host defense functions in the lung. Although both proteins are agglutinins, opsonins, and inflammatory immunomodulators, they interact uniquely with various pathogens and inflammatory cells. For instance, SP-A and SP-D appear to have opposite effects on the phagocytosis of Mycobacterium tuberculosis and on regulation of oxidant responses from alveolar macrophages. The pulmonary collectins partition into different microdomains within the airway lining; SP-D appears to prefer the aqueous phase of the ALL but may be weakly associated with the surface of epithelial cells, whereas SP-A is enriched in tubular myelin and at surfactant membrane interfaces. While the initial view held that tubular myelin would be required for surfactant regulation and function, it now appears more likely that it serves a primary host defense role as a solid-phase, high-density SP-A array that optimizes the surface properties of surfactant and the interception of inhaled microbes at the air-lung interface.

Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability

The pulmonary collectins, surfactant proteins A (SP-A) and D (SP-D), have been reported to bind lipopolysaccharide (LPS), opsonize microorganisms, and enhance the clearance of lung pathogens. In this study, we examined the effect of SP-A and SP-D on the growth and viability of Gram-negative bacteria. The pulmonary clearance of Escherichia coli K12 was reduced in SP-A-null mice and was increased in SP-D-overexpressing mice, compared with strain-matched wild-type controls. Purified SP-A and SP-D inhibited bacterial synthetic functions of several, but not all, strains of E. coli, Klebsiella pneumoniae, and Enterobacter aerogenes. In general, rough E. coli strains were more susceptible than smooth strains, and collectin-mediated growth inhibition was partially blocked by coincubation with rough LPS vesicles. Although both SP-A and SP-D agglutinated E. coli K12 in a calcium-dependent manner, microbial growth inhibition was independent of bacterial aggregation. At least part of the antimicrobial activity of SP-A and SP-D was localized to their C-terminal domains using truncated recombinant proteins. Incubation of E. coli K12 with SP-A or SP-D increased bacterial permeability. Deletion of the E. coli OmpA gene from a collectin-resistant smooth E. coli strain enhanced SP-A and SP-D-mediated growth inhibition. These data indicate that SP-A and SP-D are antimicrobial proteins that directly inhibit the proliferation of Gram-negative bacteria in a macrophage- and aggregation-independent manner by increasing the permeability of the microbial cell membrane.

Cutting Edge: The Immunostimulatory Activity of the Lung Surfactant Protein-A Involves Toll-Like Receptor 4

The collectin surfactant protein-A (SP-A) is involved in the innate host defense and the regulation of inflammatory processes in the lung. In this work we investigated the molecular mechanisms related to the immunostimulatory activity of SP-A using macrophages from C3H/HeJ mice, which carry an inactivating mutation in the Toll-like receptor (TLR)4 gene, and TLR4-transfected Chinese hamster ovary cells. We demonstrate that SP-A-induced activation of the NF-κB signaling pathway and up-regulation of cytokine synthesis such as TNF-α and IL-10 are critically dependent on the TLR4 functional complex. These findings support the concept that TLR4 is a pattern recognition receptor that signals in response to both foreign pathogens and endogenous host mediators.

European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC) 1, 2. Sporadic LAM affects ∼1 in 400,000 adult females; in TSC, LAM occurs in 30–40% of adult females 3, 4 and exceptionally in males and children 5, 6. Patients with LAM usually develop progressive dyspnoea and recurrent pneumothorax, chylous collections and occasional haemoptysis 1. Extra pulmonary lymphadenopathy and cystic masses of the axial lymphatics termed lymphangioleiomyomas can result in abdominal and pelvic lymphatic obstruction 7. LAM is often associated with angiomyolipoma in the kidneys 8, and an increased frequency of meningioma 9. LAM varies in clinical features and rate of progression: this together with an absence of clear prognostic factors results in patients being given conflicting information about prognosis. Diagnosis is made by tissue biopsy (generally from the lung but occasionally from lymph nodes or lymphangioleiomyomas) and/or a combination of history and high-resolution computed tomography scanning (HRCT). Pathological diagnosis relies on characteristic LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies. Increasingly HRCT is used to diagnose LAM without resorting to lung biopsy; however a number of conditions with multiple pulmonary cysts can mimic LAM. As LAM is rare, there have been no controlled trials of its management. Supportive treatment includes management of airflow obstruction and hypoxaemia with bronchodilators and oxygen respectively, specific treatment for surgical or pleural complications including pneumo- and chylothorax, and interventional treatment of renal lesions 10, 11. As LAM is a disease of females and is thought to be accelerated by oestrogen, oophorectomy, tamoxifen, progesterone and gonadotropin-releasing hormone (GnRH) analogues have been used without evidence that they are effective. The recent finding of abnormalities in the TSC1/2 genes resulting …

Lymphangioleiomyomatosis: A Clinical Update

Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease that is associated with mutations in tuberous sclerosis genes, renal angiomyolipomas, lymphatic spread, and remarkable female gender restriction. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections. Lung function declines at approximately twofold to threefold times the rate of healthy subjects, based on an annual drop in FEV1 of 75 to 120 mL in reported series. The diagnosis of pulmonary LAM can be made on high-resolution CT (HRCT) scan with reasonable certainty by expert radiologists, but generally requires a lung biopsy in cases in which tuberous sclerosis complex, angiomyolipomata, or chylous effusions are absent. The currently available treatment strategies are based on the antagonism of estrogen action, and are empiric and unproven. A trial of bronchodilators is warranted in patients with reversible airflow obstruction seen on pulmonary function testing. Pleurodesis should be performed with the initial pneumothorax, because the rate of recurrence is high. Angiomyolipomas that exceed 4 cm in size are more likely to bleed and should be evaluated for embolization. Air travel is well-tolerated by most patients with LAM. Lung transplantation is an important option for LAM patients, and can be safely performed by experienced surgeons despite prior unilateral or bilateral pleurodesis in most patients. Women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the setting of limited or absent tobacco use should undergo HRCT scan screening for LAM. Multicenter clinical trials based on several well-defined molecular targets are currently underway in the United States and Europe.

120-kD surface glycoprotein of Pneumocystis carinii is a ligand for surfactant protein A.

Pneumocystis carinii is the most common cause of life-threatening pneumonia in immunocompromised patients. In the current study, surfactant protein A (SP-A), the major nonserum protein constituent of pulmonary surfactant, is demonstrated to bind P. carinii in a specific and saturable manner. SP-A is surface bound and does not appear to be internalized or degraded by the P. carinii organism. Furthermore, SP-A binding to P. carinii is time- and calcium-dependent and is competitively inhibited by mannosyl albumin. In the absence of calcium or the presence of excess mannosyl albumin, SP-A binding to P. carinii is reduced by 95 and 71%, respectively. SP-A avidly binds P. carinii with a Kd of 8 x 10(-9) M and an estimated 8.4 x 10(6) SP-A binding sites per P. carinii organism, as determined from Scatchard plots. SP-A is shown to bind P. carinii in vivo, and a putative binding site for SP-A on P. carinii is demonstrated to be the mannoserich surface membrane glycoprotein gp120. These findings suggest that P. carinii can interact with the phospholipid-rich material in the alveolar spaces by specifically binding a major protein constituent of pulmonary surfactant.

Lymphangioleiomyomatosis — a wolf in sheep's clothing

Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease of women. LAM is caused by mutations in the tuberous sclerosis genes, resulting in activation of the mTOR complex 1 signaling network. Over the past 11 years, there has been remarkable progress in the understanding of LAM and rapid translation of this knowledge to an effective therapy. LAM pathogenic mechanisms mirror those of many forms of human cancer, including mutation, metabolic reprogramming, inappropriate growth and survival, metastasis via blood and lymphatic circulation, infiltration/invasion, sex steroid sensitivity, and local and remote tissue destruction. However, the smooth muscle cell that metastasizes, infiltrates, and destroys the lung in LAM arises from an unknown source and has an innocent histological appearance, with little evidence of proliferation. Thus, LAM is as an elegant, monogenic model of neoplasia, defying categorization as either benign or malignant.

Serum Surfactant Protein-A Is a Strong Predictor of Early Mortality in Idiopathic Pulmonary Fibrosis

BACKGROUND Serum surfactant protein (SP) A and SP-D had prognostic value for mortality in patients with idiopathic pulmonary fibrosis (IPF) in prior studies before the reclassification of the idiopathic interstitial pneumonias. We hypothesized that baseline serum SP-A and SP-D concentrations would be independently associated with mortality among patients with biopsy-proven IPF and would improve a prediction model for mortality. METHODS We evaluated the association between serum SP-A and SP-D concentrations and mortality in 82 patients with surgical lung biopsy-proven IPF. Regression models with clinical predictors alone and clinical and biomarker predictors were used to predict mortality at 1 year. RESULTS After controlling for known clinical predictors of mortality, we found that each increase of 49 ng/mL (1 SD) in baseline SP-A level was associated with a 3.3-fold increased risk of mortality (adjusted hazard ratio, 3.27; 95% confidence interval, 1.49 to 7.17; adjusted p = 0.003) in the first year after presentation. We did not observe a statistically significant association between serum SP-D and mortality (adjusted hazard ratio, 2.04; p = 0.053). Regression models demonstrated a significant improvement in the 1-year mortality prediction model when serum SP-A and SP-D (area under the receiving operator curve [AROC], 0.89) were added to the clinical predictors alone (AROC, 0.79; p = 0.03). CONCLUSIONS Increased serum SP-A level is a strong and independent predictor of early mortality among patients with IPF. A prediction model containing SP-A and SP-D was substantially superior to a model with clinical predictors alone.