When is Subnational, Supralocal Tobacco Control "just right"? A Qualitative Study in England.

INTRODUCTION: Subnational, supralocal (or "regional") approaches to tobacco control are often central federal nation tobacco control and can be superfluous for very small nations. However, their relevance to countries with weak intermediate tiers of governance are less clear. This study explores expert and policymaker perceptions on the function, form, footprint, and funding of regional tobacco control (RTC) in England. AIMS AND METHODS: One-to-one semistructured interviews (n = 16) and four focus groups (n = 26) exploring knowledge and perceptions of the past, present, and future of RTC in England were conducted with public health leaders, clinicians, tobacco control practitioners, civil servants, and politicians. Interviews were audio-recorded, transcribed verbatim, and analyzed thematically. RESULTS: Participants reported several key functions for RTC, including illicit tobacco control, media campaigns, advocacy, policy development, and network facilitation for local actors. A small minority of participants reported little role for RTC. Broader perceived features of effective RTC included subject expertise, strong regional ties, systems leadership, and a distinctive program of work. Views varied on whether regional programs should be developed nationally or locally, and their optimal footprint. Participants generally agreed stable funding was a prerequisite for success, although there was lesser agreement on funding sources. CONCLUSIONS: Pooling resources at the regional level in countries with weak intermediate tiers of governance may increase reach, cost-effectiveness and impact of campaigns, policy interventions, and advocacy, whilst retaining the ability to tailor approaches to regional populations. IMPLICATIONS: There are likely to be greater funding and governance challenges associated with introducing or strengthening RTC in countries with weak intermediate tiers of governance. Despite this, evidence from England shows it is possible to develop RTC approaches reported as effective by key stakeholders. Possible benefits of regional approaches in this context include cost-effective delivery of illicit tobacco control, media campaigns, advocacy, research, policy development, and coordinated support for local action on tobacco.

Accessing chemical diversity from the uncultivated symbionts of small marine animals.

Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV compounds from small, marine tunicates from the Eastern Fields of Papua New Guinea. Tunicates are a reservoir for new bioactive chemicals, yet their small size often impedes identification or even detection of the chemicals within. We solved this problem by combining chemistry, metagenomics, and synthetic biology to directly identify and synthesize the natural products. We show that these anti-HIV compounds, the divamides, are a novel family of lanthipeptides produced by symbiotic bacteria living in the tunicate. Neighboring animal colonies contain structurally related divamides that differ starkly in their biological properties, suggesting a role for biosynthetic plasticity in a native context wherein biological interactions take place.

One-carbon chemistry of oxalate oxidoreductase captured by X-ray crystallography.

Thiamine pyrophosphate (TPP)-dependent oxalate oxidoreductase (OOR) metabolizes oxalate, generating two molecules of CO2 and two low-potential electrons, thus providing both the carbon and reducing equivalents for operation of the Wood-Ljungdahl pathway of acetogenesis. Here we present structures of OOR in which two different reaction intermediate bound states have been trapped: the covalent adducts between TPP and oxalate and between TPP and CO2. These structures, along with the previously determined structure of substrate-free OOR, allow us to visualize how active site rearrangements can drive catalysis. Our results suggest that OOR operates via a bait-and-switch mechanism, attracting substrate into the active site through the presence of positively charged and polar residues, and then altering the electrostatic environment through loop and side chain movements to drive catalysis. This simple but elegant mechanism explains how oxalate, a molecule that humans and most animals cannot break down, can be used for growth by acetogenic bacteria.

Molecular basis for the broad substrate selectivity of a peptide prenyltransferase.

The cyanobactin prenyltransferases catalyze a series of known or unprecedented reactions on millions of different substrates, with no easily observable recognition motif and exquisite regioselectivity. Here we define the basis of broad substrate tolerance for the otherwise uncharacterized TruF family. We determined the structures of the Tyr-prenylating enzyme PagF, in complex with an isoprenoid donor analog and a panel of linear and macrocyclic peptide substrates. Unexpectedly, the structures reveal a truncated barrel fold, wherein binding of large peptide substrates is necessary to complete a solvent-exposed hydrophobic pocket to form the catalytically competent active site. Kinetic, mutational, chemical, and computational analyses revealed the structural basis of selectivity, showing a small motif within peptide substrates that is sufficient for recognition by the enzyme. Attaching this 2-residue motif to two random peptides results in their isoprenylation by PagF, demonstrating utility as a general biocatalytic platform for modifications on any peptide substrate.

Metabolic model for diversity-generating biosynthesis.

A conventional metabolic pathway leads to a specific product. In stark contrast, there are diversity-generating metabolic pathways that naturally produce different chemicals, sometimes of great diversity. We demonstrate that for one such pathway, tru, each ensuing metabolic step is slower, in parallel with the increasing potential chemical divergence generated as the pathway proceeds. Intermediates are long lived and accumulate progressively, in contrast with conventional metabolic pathways, in which the first step is rate-limiting and metabolic intermediates are short-lived. Understanding these fundamental differences enables several different practical applications, such as combinatorial biosynthesis, some of which we demonstrate here. We propose that these principles may provide a unifying framework underlying diversity-generating metabolism in many different biosynthetic pathways.

Roads to Rome: Role of Multiple Cassettes in Cyanobactin RiPP Biosynthesis.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are ubiquitous natural products. Bioactive RiPPs are produced from a precursor peptide, which is modified by enzymes. Usually, a single product is encoded in a precursor peptide. However, in cyanobactins and several other RiPP pathways, a single precursor peptide encodes multiple bioactive products flanking with recognition sequences known as "cassettes". The role of multiple cassettes in one peptide is mysterious, but in general their presence is a marker of biosynthetic plasticity. Here, we show that in cyanobactin biosynthesis the presence of multiple cassettes confers distributive enzyme processing to multiple steps of the pathway, a feature we propose to be a hallmark of multicassette RiPPs. TruD heterocyclase is stochastic and distributive. Although a canonical biosynthetic route is favored with certain substrates, every conceivable biosynthetic route is accepted. Together, these factors afford greater plasticity to the biosynthetic pathway by equalizing the processing of each cassette, enabling access to chemical diversity.

Properties of Intermediates in the Catalytic Cycle of Oxalate Oxidoreductase and Its Suicide Inactivation by Pyruvate.

Oxalate:ferredoxin oxidoreductase (OOR) is an unusual member of the thiamine pyrophosphate (TPP)-dependent 2-oxoacid:ferredoxin oxidoreductase (OFOR) family in that it catalyzes the coenzyme A (CoA)-independent conversion of oxalate into 2 equivalents of carbon dioxide. This reaction is surprising because binding of CoA to the acyl-TPP intermediate of other OFORs results in formation of a CoA ester, and in the case of pyruvate:ferredoxin oxidoreductase (PFOR), CoA binding generates the central metabolic intermediate acetyl-CoA and promotes a 105-fold acceleration of the rate of electron transfer. Here we describe kinetic, spectroscopic, and computational results to show that CoA has no effect on catalysis by OOR and describe the chemical rationale for why this cofactor is unnecessary in this enzymatic transformation. Our results demonstrate that, like PFOR, OOR binds pyruvate and catalyzes decarboxylation to form the same hydroxyethylidine-TPP (HE-TPP) intermediate and one-electron transfer to generate the HE-TPP radical. However, in OOR, this intermediate remains stranded at the active site as a covalent inhibitor. These and other results indicate that, like other OFOR family members, OOR generates an oxalate-derived adduct with TPP (oxalyl-TPP) that undergoes decarboxylation and one-electron transfer to form a radical intermediate remaining bound to TPP (dihydroxymethylidene-TPP). However, unlike in PFOR, where CoA binding drives formation of the product, in OOR, proton transfer and a conformational change in the "switch loop" alter the redox potential of the radical intermediate sufficiently to promote the transfer of an electron into the iron-sulfur cluster network, leading directly to a second decarboxylation and completing the catalytic cycle.

The Structure of an Oxalate Oxidoreductase Provides Insight into Microbial 2-Oxoacid Metabolism.

Thiamine pyrophosphate (TPP), a derivative of vitamin B1, is a versatile and ubiquitous cofactor. When coupled with [4Fe-4S] clusters in microbial 2-oxoacid:ferredoxin oxidoreductases (OFORs), TPP is involved in catalyzing low-potential redox reactions that are important for the synthesis of key metabolites and the reduction of N2, H(+), and CO2. We have determined the high-resolution (2.27 Å) crystal structure of the TPP-dependent oxalate oxidoreductase (OOR), an enzyme that allows microbes to grow on oxalate, a widely occurring dicarboxylic acid that is found in soil and freshwater and is responsible for kidney stone disease in humans. OOR catalyzes the anaerobic oxidation of oxalate, harvesting the low-potential electrons for use in anaerobic reduction and fixation of CO2. We compare the OOR structure to that of the only other structurally characterized OFOR family member, pyruvate:ferredoxin oxidoreductase. This side-by-side structural analysis highlights the key similarities and differences that are relevant for the chemistry of this entire class of TPP-utilizing enzymes.

TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521).

Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.

Persistence of livestock-associated antibiotic-resistant Staphylococcus aureus among industrial hog operation workers in North Carolina over 14 days.

OBJECTIVES: This study aimed to evaluate the persistence of nasal carriage of Staphylococcus aureus, methicillin-resistant S. aureus and multidrug-resistant S. aureus over 14 days of follow-up among industrial hog operation workers in North Carolina. METHODS: Workers anticipating at least 24 h away from work were enrolled June-August 2012. Participants self-collected a nasal swab and completed a study journal on the evening of day 1, and each morning and evening on days 2-7 and 14 of the study. S. aureus isolated from nasal swabs were assessed for antibiotic susceptibility, spa type and absence of the scn gene. Livestock association was defined by absence of scn. RESULTS: Twenty-two workers provided 327 samples. S. aureus carriage end points did not change with time away from work (mean 49 h; range >0-96 h). Ten workers were persistent and six were intermittent carriers of livestock-associated S. aureus. Six workers were persistent and three intermittent carriers of livestock-associated multidrug-resistant S. aureus. One worker persistently carried livestock-associated methicillin-resistant S. aureus. Six workers were non-carriers of livestock-associated S. aureus. Eighty-two per cent of livestock-associated S. aureus demonstrated resistance to tetracycline. A majority of livestock-associated S. aureus isolates (n=169) were CC398 (68%) while 31% were CC9. No CC398 and one CC9 isolate was detected among scn-positive isolates. CONCLUSIONS: Nasal carriage of livestock-associated S. aureus, multidrug-resistant S. aureus and methicillin-resistant S. aureus can persist among industrial hog operation workers over a 14-day period, which included up to 96 h away from work.

A unified electrocatalytic description of the action of inhibitors of nickel carbon monoxide dehydrogenase.

Several small molecules and ions, notably carbon monoxide, cyanide, cyanate, and hydrogen sulfide, are potent inhibitors of Ni-containing carbon monoxide dehydrogenases (Ni-CODH) that catalyze very rapid, efficient redox interconversions of CO(2) and CO. Protein film electrochemistry, which probes the dependence of steady-state catalytic rate over a wide potential range, reveals how these inhibitors target particular oxidation levels of Ni-CODH relating to intermediates (C(ox), C(red1), and C(red2)) that have been established for the active site. The following properties are thus established: (1) CO suppresses CO(2) reduction (CO is a product inhibitor), but its binding affinity decreases as the potential becomes more negative. (2) Cyanide totally inhibits CO oxidation, but its effect on CO(2) reduction is limited to a narrow potential region (between -0.5 and -0.6 V), below which CO(2) reduction activity is restored. (3) Cyanate is a strong inhibitor of CO(2) reduction but inhibits CO oxidation only within a narrow potential range just above the CO(2)/CO thermodynamic potential--EPR spectra confirm that cyanate binds selectively to C(red2). (4) Hydrogen sulfide (H(2)S/HS(-)) inhibits CO oxidation but not CO(2) reduction--the complex on/off characteristics are consistent with it binding at the same oxidation level as C(ox) and forming a modified version of this inactive state rather than reacting directly with C(red1). The results provide a new perspective on the properties of different catalytic intermediates of Ni-CODH--uniting and clarifying many previous investigations.

Defibrotide modulates pulmonary endothelial cell activation and protects against lung inflammation in pre-clinical models of LPS-induced lung injury and idiopathic pneumonia syndrome.

Introduction: A multiple organ dysfunction syndrome (MODS) workshop convened by the National Institute of Child Health and Human Development in 2015 identified acute respiratory distress syndrome (ARDS) and complications of allogeneic blood and marrow transplantation (allo-BMT) as contributors to MODS in pediatric patients. Pulmonary dysfunction also remains a significant complication of allo-BMT. Idiopathic pneumonia syndrome (IPS) defines non-infectious, acute, lung injury that occurs post-transplant. Injury and activation to endothelial cells (ECs) contribute to each form of lung inflammation. Methods: Two murine models were employed. In an ARDS model, naïve B6 mice receive an intravenous (i.v.) injection of lipopolysaccharide (LPS). In the established model of IPS, naïve B6D2F1 mice receive lethal total body irradiation followed by BMT from either allogeneic (B6) or syngeneic (B6D2F1) donors. Lung inflammation was subsequently assessed in each scenario. Results: Intravenous injection of LPS to B6 mice resulted in enhanced mRNA expression of TNFα, IL-6, Ang-2, E-, and P-selectin in whole lung homogenates. The expression of Ang-2 in this context is regulated in part by TNFα. Additionally, EC activation was associated with increased total protein and cellularity in broncho-alveolar lavage fluid (BALF). Similar findings were noted during the development of experimental IPS. We hypothesized that interventions maintaining EC integrity would reduce the severity of ARDS and IPS. Defibrotide (DF) is FDA approved for the treatment of BMT patients with sinusoidal obstruction syndrome and renal or pulmonary dysfunction. DF stabilizes activated ECs and protect them from further injury. Intravenous administration of DF before and after LPS injection significantly reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P-selectin compared to controls. BALF showed decreased cellularity, reflecting less EC damage and leak. Allogeneic BMT mice were treated from day -1 through day 14 with DF intraperitoneally, and lungs were harvested at 3 weeks. Compared to controls, DF treatment reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P- selectin, BALF cellularity, and lung histopathology. Conclusion: The administration of DF modulates EC injury in models of ARDS and IPS. Cytokine inhibition in combination with agents that stabilize EC integrity may be an attractive strategy for patients in each setting.

A Balanced Scorecard for Maximizing Data Performance.

A good performance monitoring system is crucial to knowing whether an organization's efforts are making their data capabilities better, the same, or worse. However, comprehensive performance measurements are costly. Organizations need to expend time, resources, and personnel to design the metrics, to gather evidence for the metrics, to assess the metrics' value, and to determine if any actions should be taken as a result of those metrics. Consequently organizations need to be strategic in selecting their portfolio of performance indicators for evaluating how well their data initiatives are producing value to the organization. This paper proposes a balanced scorecard approach to aid organizations in designing a set of meaningful and coordinated metrics for maximizing the potential of their data assets. This paper also discusses implementation challenges and the need for further research in this area.

Identification and characterization of oxalate oxidoreductase, a novel thiamine pyrophosphate-dependent 2-oxoacid oxidoreductase that enables anaerobic growth on oxalate.

Moorella thermoacetica is an anaerobic acetogen, a class of bacteria that is found in the soil, the animal gastrointestinal tract, and the rumen. This organism engages the Wood-Ljungdahl pathway of anaerobic CO(2) fixation for heterotrophic or autotrophic growth. This paper describes a novel enzyme, oxalate oxidoreductase (OOR), that enables M. thermoacetica to grow on oxalate, which is produced in soil and is a common component of kidney stones. Exposure to oxalate leads to the induction of three proteins that are subunits of OOR, which oxidizes oxalate coupled to the production of two electrons and CO(2) or bicarbonate. Like other members of the 2-oxoacid:ferredoxin oxidoreductase family, OOR contains thiamine pyrophosphate and three [Fe(4)S(4)] clusters. However, unlike previously characterized members of this family, OOR does not use coenzyme A as a substrate. Oxalate is oxidized with a k(cat) of 0.09 s(-1) and a K(m) of 58 µM at pH 8. OOR also oxidizes a few other 2-oxoacids (which do not induce OOR) also without any requirement for CoA. The enzyme transfers its reducing equivalents to a broad range of electron acceptors, including ferredoxin and the nickel-dependent carbon monoxide dehydrogenase. In conjunction with the well characterized Wood-Ljungdahl pathway, OOR should be sufficient for oxalate metabolism by M. thermoacetica, and it constitutes a novel pathway for oxalate metabolism.

Efficient and clean photoreduction of CO(2) to CO by enzyme-modified TiO(2) nanoparticles using visible light.

A hybrid enzyme-nanoparticle system is described for achieving clean reduction of CO(2) to CO using visible light as the energy source. An aqueous dispersion of TiO(2) nanoparticles modified by attachment of carbon monoxide dehydrogenase (CODH) and a Ru photosensitizer produces CO at a rate of 250 mumol of CO (g of TiO(2))(-1) h(-1) when illuminated with visible light at pH 6 and 20 degrees C.

Secondary lymphoid organs contribute to, but are not required for the induction of graft-versus-host responses following allogeneic bone marrow transplantation: a shifting paradigm for T cell allo-activation.

Graft-versus-host disease (GVHD) remains the major complication of allogeneic bone marrow transplantation (allo-BMT). GVHD fundamentally depends upon the activation of donor T cells by host antigen-presenting cells (APCs), but the precise location of these interactions remains uncertain. We examined the role of secondary lymphoid organs (SLO) in the induction of GVHD by using homozygous aly/aly mice that are deficient in lymph nodes (LNs) and Peyer's patches (PPs). Lethally irradiated, splenectomized, aly/aly (LN/PP/Sp-/-) mice and sham-splenectomized, aly/+ (LN/PP/Sp+/+) mice received BMT from either syngeneic (aly/aly) or allogeneic, major histocompatibility complex (MHC) disparate donors. Surprisingly, although LN/PP/Sp-/- allo-BMT recipients experience a survival advantage, they developed significant systemic and target organ GVHD that is comparable to LN/PP/Sp+/+ controls. Early after allo-BMT, the activation and proliferation of donor T cells was significantly greater in the BM cavity of LN/PP/Sp-/- mice compared to LN/PP/Sp+/+ controls. Donor T cells in LN/PP/Sp-/- mice demonstrated cytolytic activity in vitro, but Graft vs Leukemia (GVL) activity could be overcome by increasing the tumor burden. These data suggest that SLO contribute to, but are not required for, allogeneic T cell responses, and suggest that the BM may represent an alternative, albeit less efficient site for T cell activation following allo-BMT.

Acetogenesis and the Wood-Ljungdahl pathway of CO(2) fixation.

Conceptually, the simplest way to synthesize an organic molecule is to construct it one carbon at a time. The Wood-Ljungdahl pathway of CO(2) fixation involves this type of stepwise process. The biochemical events that underlie the condensation of two one-carbon units to form the two-carbon compound, acetate, have intrigued chemists, biochemists, and microbiologists for many decades. We begin this review with a description of the biology of acetogenesis. Then, we provide a short history of the important discoveries that have led to the identification of the key components and steps of this usual mechanism of CO and CO(2) fixation. In this historical perspective, we have included reflections that hopefully will sketch the landscape of the controversies, hypotheses, and opinions that led to the key experiments and discoveries. We then describe the properties of the genes and enzymes involved in the pathway and conclude with a section describing some major questions that remain unanswered.

Water-gas shift reaction catalyzed by redox enzymes on conducting graphite platelets.

The water-gas shift (WGS) reaction (CO + H(2)O <==> CO(2) + H(2)) is of major industrial significance in the production of H(2) from hydrocarbon sources. High temperatures are required, typically in excess of 200 degrees C, using d-metal catalysts on oxide supports. In our study the WGS process is separated into two half-cell electrochemical reactions (H(+) reduction and CO oxidation), catalyzed by enzymes attached to a conducting particle. The H(+) reduction reaction is catalyzed by a hydrogenase, Hyd-2, from Escherichia coli, and CO oxidation is catalyzed by a carbon monoxide dehydrogenase (CODH I) from Carboxydothermus hydrogenoformans. This results in a highly efficient heterogeneous catalyst with a turnover frequency, at 30 degrees C, of at least 2.5 s(-1) per minimum functional unit (a CODH/Hyd-2 pair) which is comparable to conventional high-temperature catalysts.

Malpractice litigation involving iatrogenic surgical vocal fold paralysis: a closed-claims review with recommendations for prevention and management.

OBJECTIVES: We describe the nature of malpractice claims filed involving surgical iatrogenic vocal fold paralysis, review surgical literature for recommendations for prevention of this complication, and suggest management of this complication. METHODS: Data collection was made regarding any closed claims that involved vocal fold paralysis. The results were then analyzed and categorized. The PubMed literature regarding this complication was reviewed, and recommendations on prevention were compiled. Finally, suggestions regarding management based on the current literature and the senior author's 17-year experience in his laryngeal practice are offered. RESULTS: From 1986 to 2007, 112 closed claims involving vocal fold paralysis were reported by the 16 largest malpractice insurers. More than US $10 million ($18 million adjusted for inflation [AJI]) has been paid thus far. The average indemnity was $285,000 ($513,000 AJI). The surgical physician defendants were from multiple specialties, including general surgery (31%), cardiothoracic surgery (12%), neurosurgery (12%), otolaryngology (10%), and orthopedic surgery (5%). The most common procedures were thyroid and parathyroid surgery (32%), cervical disc procedures (16%), thoracic procedures (12%), endarterectomy (9%), and open neck biopsy (6%). The most common claims cited were improper performance (61%), failure to recognize a complication (36%), and consent issues (19%). CONCLUSIONS: Vocal fold paralysis is a complication of many different surgical procedures across multiple specialty lines. Closed-claims analysis can offer a unique glimpse on what went wrong and why patients sue. Modification of techniques and incorporation of new technology may significantly reduce this complication. Preoperative written information on potential complications, and early referral to and management by laryngeal specialists, we believe, may significantly reduce malpractice litigation.

A role for TNF receptor type II in leukocyte infiltration into the lung during experimental idiopathic pneumonia syndrome.

Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication following allogeneic stem cell transplantation (allo-SCT). Experimental models have revealed that TNF-alpha contributes to pulmonary vascular endothelial cell (EC) apoptosis, and modulates the infiltration of donor leukocytes into the lung parenchyma. The inflammatory effects of TNF-alpha are mediated by signaling through the type I (TNFRI) or type II (TNFRII) TNF receptors. We investigated the relative contribution of TNFRI and TNFRII to leukocyte infiltration into the lung following allo-SCT by using established murine models. Wild-type (wt) B6 mice or B6 animals deficient in either TNFRI or TNFRII were lethally irradiated and received SCT from allogeneic (LP/J) or syngeneic (B6) donors. At week 5 following SCT, the severity of IPS was significantly reduced in TNFRII-/- recipients compared to wt controls, but no effect was observed in TNFRI-/- animals. Bronchoalveolar lavage fluid (BALF) levels of RANTES and pulmonary ICAM-1 expression in TNFRII-/- recipients were also reduced, and correlated with a reduction of CD8(+) cells in the lung. Pulmonary inflammation was also decreased in TNFRII-/- mice using an isolated MHC class I disparate model (bm1 --> B6), and in bm1 wt mice transplanted with B6 TNF-alpha-/- donor cells. Collectively, these data demonstrate a role for TNF-alpha signaling through TNFRII in leukocyte infiltration into the lung following allo-SCT, and suggest that disruption of the TNF-alpha:TNFRII pathway may be an effective tool to prevent or treat IPS.