Alveolar epithelial cell dysfunction plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) but remains incompletely understood. Some monogenic forms of pulmonary fibrosis are associated with expression of mutant surfactant protein C (SFTPC). The commonest pathogenic mutant, I73T, mislocalises to the alveolar epithelial cell plasma membrane and displays a toxic-gain-of-function. Because the mechanisms explaining the link between this mutant and IPF are incompletely understood, we sought to interrogate SFTPC trafficking in health and disease to understand the functional significance of SFTPC-I73T relocalisation.We performed mechanistic analysis of SFTPC trafficking in a cell model that reproduces the in vivo phenotype and validated findings in human primary alveolar organoids.We show that wild-type SFTPC takes an unexpected indirect trafficking route via the plasma membrane and undergoes the first of multiple cleavage events before reaching the multivesicular body (MVB) for further processing. SFTPC-I73T takes this same route, but its progress is retarded both at the cell surface and due to failure of trafficking into the MVB. Unable to undergo onward trafficking, it is recycled to the plasma membrane as a partially cleaved intermediate.These data show for the first time that all SFTPC transits the cell surface during normal trafficking, and the I73T mutation accumulates at the cell surface through both retarded trafficking and active recycling. This understanding of normal SFTPC trafficking and how the I73T mutant disturbs it provides novel insight into SFTPC biology in health and disease, and in the contribution of the SFTPC mutant to IPF development.

Bronchial thermoplasty is a mechanical therapeutic intervention that has been advocated as an effective treatment option for severe asthma. The mechanism is promoted as being related to the attenuation of airway smooth muscle which has been shown to occur in the short-term. However, long-term studies of the effects of bronchial thermoplasty on airway remodeling are few with only limited assessment of airway remodeling indices.

To evaluate the effect of bronchial thermoplasty on (a) airway epithelial and smooth muscle cells in culture, and (b), airway remodeling in patients with severe asthma who have been prescribed bronchial thermoplasty up to 12-months post-treatment.

The distribution of heat within the airway by bronchial thermoplasty was assessed in a porcine model. Culture of human airway smooth muscle cells and bronchial epithelial cells evaluated the impact of thermal injury. Histological evaluation and morphometric assessment were performed on bronchial biopsies obtained from severe asthma patients at baseline, 6-weeks, and 12-months following bronchial thermoplasty.

Bronchial thermoplasty resulted in heterogenous heating of the airway wall. Airway smooth muscle cell cultures sustained thermal injury, whilst bronchial epithelial cells were relatively resistant to heat. Airway smooth muscle and neural bundles were significantly reduced at 6-weeks and 12-months post-treatment. At 6-weeks post treatment, submucosal collagen was reduced, and vessel density increased, with both indices returning to baseline at 12-months. Goblet cell numbers, submucosal gland area and subbasement membrane thickness, were not significantly altered at any timepoint examined.

Bronchial thermoplasty primarily affects airway smooth muscle and nerves with the effects still present at 12-months post-treatment.

Bronchial thermoplasty primarily affects airway smooth muscle and nerves with the effects still present at 12-months post-treatment.

Herein we investigated the mechanisms by which 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of adenosine monophosphate (AMP)-activated protein kinase (AMPK), administered to mice post exposure to bromine (Br

), decreases lung injury and mortality.

We exposed male C57BL/6 mice as well as heme oxygenase-1 deficient (HO-1

) and corresponding WT littermate mice to Br

(600 ppm for 45 or 30 min respectively) gas in environmental chambers and returned them to room air. AICAR was administered 6 h post-exposure (10 mg·kg

, IP). We assessed survival, indices of lung injury, high mobility group box 1 (HMGB1) in the plasma, HO-1 levels in lung tissues and phosphorylation of AMPK and its upstream liver kinase B1 (LKB1). Rat lung Type II epithelial cells (L2) and human club-like epithelial cells (H441) were also exposed to Br

(100 ppm for 10 min). Twenty-four h later we measured apoptosis and necrosis, AMPK and LKB1 phosphorylation and HO-1 expression.

There was a marked downregulation of phosphorylated AMPK and LKB1 in both lung tissues and L2 and H441 cells post-exposure. AICAR increased survival in C57BL/6 but not in HO-1

mice. Additionally, in WT mice AICAR decreased lung injury and restored pAMPK and pLKB1 to control levels and increased HO-1 levels in both lung tissues and cells exposed to Br

Treatment of L2 and H441 cells with siRNAs against Nrf2 or HO-1 abrogated the protective effects of AICAR.

Our data indicate that the primary mechanism for the protective action of AICAR in toxic gas injury is by upregulating lung HO-1 levels.

Our data indicate that the primary mechanism for the protective action of AICAR in toxic gas injury is by upregulating lung HO-1 levels.

Bringing reliable and accurate tuberculosis (TB) diagnosis closer to patients is a key priority for global TB control. Molbio Diagnostics have developed the Truenat point-of-care molecular assays for detection of TB and rifampicin (RIF) resistance.

We conducted a prospective multicentre diagnostic accuracy study at 19 primary health care centres and seven reference laboratories in Peru, India, Ethiopia and Papua New Guinea to estimate the diagnostic accuracy of the point-of-care Truenat MTB, MTB Plus and MTB-RIF Dx assays for pulmonary TB using culture and phenotypic drug susceptibility testing as the reference standard, compared to Xpert MTB/RIF or Ultra.

Of 1807 enrolled participants with TB signs/symptoms, 24% were culture positive for

, of which 15% were RIF-resistant. In microscopy centres, the pooled sensitivity of Truenat MTB and Truenat MTB Plus was 73% [95% CI 67, 78] and 80% [95% CI 75, 84], respectively. Selleck GSK8612 Among smear-negative specimens, sensitivities were 36% [95% CI 27, 47] and 47% [95% CI 37, 58], respectively.