TLR5 Activation Exacerbates Airway Inflammation in Asthma.

INTRODUCTION: Innate immune activation through exposure to indoor and outdoor pollutants is emerging as an important determinant of asthma severity. For example, household levels of the bacterial product lipopolysaccharide (LPS) are associated with increased asthma severity. We hypothesized that activation of the innate immune receptor TLR5 by its bacterial ligand flagellin will exacerbate airway inflammation and asthma symptoms. METHODS: We determined the effect of flagellin co-exposure with ovalbumin in a murine model of allergic asthma. We evaluated the presence of flagellin activity in house dust of asthma patients. Finally, we analyzed the association of a dominant-negative polymorphism in TLR5 (rs5744168) with asthma symptoms in patients with asthma. RESULTS: We showed that bacterial flagellin can be found in the house dust of patients with asthma and that this bacterial product exacerbates allergic airway inflammation in an allergen-specific mouse model of asthma. Furthermore, a dominant-negative genetic polymorphism in TLR5, the receptor for flagellin, is associated with decreased symptoms in patients with asthma. CONCLUSION: Together, our results reveal a novel genetic protective factor (TLR5 deficiency) and a novel environmental pollutant (microbial flagellin) that influence asthma severity. (Clinical trials NCT01688986 and NCT01087307).

INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer.

Epigenetic regulators are attractive targets for the development of new cancer therapies. Among them, the ATP-dependent chromatin remodeling complexes control the chromatin architecture and have important roles in gene regulation. They are often found to be mutated and de-regulated in cancers, but how they influence the cancer gene expression program during cancer initiation and progression is not fully understood. Here we show that the INO80 chromatin remodeling complex is required for oncogenic transcription and tumor growth in non-small-cell lung cancer (NSCLC). Ino80, the SWI/SNF ATPase in the complex, is highly expressed in NSCLC cells compared with normal lung epithelia cells. Further, its expression, as well as that of another subunit Ino80B, negatively correlates with disease prognosis in lung cancer patients. Functionally, INO80 silencing inhibits NSCLC cell proliferation and anchorage-independent growth in vitro and tumor formation in mouse xenografts. It occupies enhancer regions near lung cancer-associated genes, and its occupancy correlates with increased genome accessibility and enhanced expression of downstream genes. Together, our study defines a critical role of INO80 in promoting oncogenic transcription and NSCLC tumorigenesis, and reveals a potential treatment strategy for inhibiting the cancer transcription network by targeting the INO80 chromatin remodeling complex.

Bakery flour dust exposure causes non-allergic inflammation and enhances allergic airway inflammation in mice.

BACKGROUND: Baker's asthma is one of the most commonly reported occupational lung diseases in countries where fresh bread is baked daily in large quantities, and is characterized by rhinitis, bronchial hyperresponsiveness, and reversible airflow obstruction. Epidemiological studies have identified pre-existing atopy as an important risk factor for developing baker's asthma, yet the aetiology and pathogenesis of baker's asthma remain poorly understood. OBJECTIVE: We sought to develop a mouse model of baker's asthma that could be used to characterize the development and progression of baker's asthma. METHODS: We were unable to sensitize mice to bakery flour dust or flour dust extract. We assessed total inflammatory cells, cellular differential, total serum IgE and the pro-inflammatory cytokine response to oropharyngeally instilled bakery flour dust or flour dust extract by itself or in the context of ovalbumin (OVA) sensitization and challenge. RESULTS: Both bakery flour dust and flour dust extract consistently elicited a neutrophilic inflammation in a Toll-like receptor 4-independent manner; suggesting that endotoxin is not playing a role in the inflammatory response to flour dust. Moreover, bakery flour dust and dust extract significantly enhance the inflammatory response in OVA-sensitized and challenged mice. CONCLUSIONS: Bakery flour dust and flour dust extract are strongly pro-inflammatory and can cause non-allergic airway inflammation and can enhance allergen-mediated airway inflammation.

Alemtuzumab in the treatment of refractory acute rejection and bronchiolitis obliterans syndrome after human lung transplantation.

Despite substantial improvements in early survival after lung transplantation, refractory acute rejection (RAR) and bronchiolitis obliterans syndrome (BOS) remain major contributors to transplant-related morbidity and mortality. We have utilized alemtuzumab, a humanized anti-CD52 antibody which results in potent lymphocyte depletion, in consecutive patients with RAR (n = 12) or BOS (n = 10). All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis. Alemtuzumab significantly improved histological rejection scores in RAR. Total rejection grade/biopsy was 1.98 +/- 0.25 preceding alemtuzumab versus 0.33 +/- 0.14 posttreatment, p-value <0.0001 (with a similar number of biopsies/patient per respective time interval). Freedom from BOS was observed in 65% of RAR patients 2 years after alemtuzumab treatment. Although there was no statistically significant change in forced expiratory volume in 1 second (FEV1) before and after alemtuzumab treatment in patients with BOS, a stabilization or improvement in BOS grade occurred in 70% of patients. Patient survival 2 years after alemtuzumab for BOS was 69%. Despite a dramatic decline in CD4 counts in alemtuzumab-treated patients, only one patient developed a lethal infection. Thus, we provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with RAR or BOS.

Association of a COL1A1 polymorphism with lumbar disc disease in young military recruits.

BACKGROUND: Lumbar disc disease (LDD), one of the most common conditions for which patients seek medical care, has been associated with sequence changes of the COL genes. COL1A1, however, has not been studied in young patients with LDD; COL1A1 polymorphisms have been associated with bone mineral density (BMD) in several populations and with LDD in older adults. OBJECTIVE: To study COL1A1 polymorphisms in young Greek army recruits with LDD. SUBJECTS: These young soldiers were diagnosed with early LDD at the time of their presentation to a military training site. All patients had radiological confirmation of their disease; a control group was also studied. METHODS: Sp1-binding site polymorphism of the COL1A1 gene was investigated by standard methods. RESULTS: There was an increased frequency of the "ss" genotype (33.3%) in LDD patients; none of the controls had this genotype. In addition, a significantly smaller number of controls was heterozygotes for this allele. CONCLUSIONS: A previously studied sequence change of the regulatory region of the COL1A1 gene, the same as has previously been associated with low BMD in many populations and LDD in older adults, showed a strong association with LDD in young male soldiers who were recently diagnosed with this disease.

Influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome.

Influenza infection is increasingly recognized to cause significant morbidity and mortality in the community, especially in pediatric patients and elderly persons. Influenza infection, however, has not been well described among thoracic organ transplant recipients. We provide the first detailed clinical, radiographic, and histologic description of influenza pneumonia among three lung transplant recipients. The presentation varied considerably among the three patients and, in some cases, was atypical for influenza. Despite treatment, a persistent decline in pulmonary function occurred in all three patients after the acute illness. Interestingly, on follow-up biopsy specimens, each patient had histologic evidence of acute rejection and/or obliterative bronchiolitis. Additional research, therefore, is needed to clarify the relationship between influenza infection, acute rejection, and obliterative bronchiolitis.