Shaughnessy, Gaja F.

Abstract Background Acute respiratory exacerbations in idiopathic pulmonary fibrosis (IPF), often triggered by infection, are life threatening events characterized by rapid deterioration of lung function and associated with poor prognosis. Since microbial antigens modulate immunity by activating different pattern recognition receptors (PRR) expressed by innate immune cells (including B-cells), we sought to investigate how the activation of human B-cells through PRR stimulation by different microbial (CpG and β-glucan) and non-microbial (Mitochondrial DAMPs; MTDs) antigens resulted in the release of an inflammatory/fibrotic milieu that contributed to the pathogenesis of fibrosis in patients with IPF. Results Our results show that an inflammatory milieu is induced by stimulating circulating B-cells with both noninfectious (MTDs) and infectious antigens (CpG and β-glucan) commonly found in bacteria and fungi. Moreover, we show that the inflammatory milieu produced was specific to the inducing antigen, and that the microbial antigens (CpG and β-glucan) triggered distinct signaling pathways in B-cells. Specifically, CpG induced mTOR-activation while β-glucan was mTOR-independent and activated Src and p38. Furthermore, our results also show that B-cell aggregates are present within fibrotic areas of the lung in IPF patients and activated B-cells induce fibroblast migration, which was modified by antifibrotics (nintedanib and pirfenidone). Conclusion Our results highlight the potential contribution of activated B-cells through PRRs to the proinflammatory and profibrotic milieu seen in patients with idiopathic pulmonary fibrosis.

Abstract B-cell activation is increasingly linked to numerous fibrotic lung diseases, and it is well known that aggregates of lymphocytes form in the lung of many of these patients. Activation of B-cells by pattern recognition receptors (PRRs) drives the release of inflammatory cytokines, chemokines, and metalloproteases important in the pathophysiology of pulmonary fibrosis. However, the specific mechanisms of B-cell activation in patients with idiopathic pulmonary fibrosis (IPF) are poorly understood. Herein, we have demonstrated that B-cell activation by microbial antigens contributes to the inflammatory and profibrotic milieu seen in patients with IPF. B-cell stimulation by CpG and β-glucan via PRRs resulted in activation of mTOR-dependent and independent pathways. Moreover, we showed that the B-cell–secreted inflammatory milieu is specific to the inducing antigen and causes differential fibroblast migration and activation. B-cell responses to infectious agents and subsequent B-cell–mediated fibroblast activation are modifiable by antifibrotics, but each seems to exert a specific and different effect. These results suggest that, upon PRR activation by microbial antigens, B-cells can contribute to the inflammatory and fibrotic changes seen in patients with IPF, and antifibrotics are able to at least partially reverse these responses.

Abstract Introduction Prior studies established that compliance during the early days of positive airway pressure (PAP) therapy predicts long-term adherence, which in turn relates to outcomes. However, patient impressions gathered immediately after PAP titration may be the earliest indication of adherence and could help focus efforts at improving compliance. The aim of this study was to examine whether a survey on PAP experience during polysomnography predicts adherence. Methods This prospective cohort study included PAP naïve adults with obstructive sleep apnea who had PAP titration during polysomnography and had 30 day adherence data available. Patients answered a pre-existing 5-question survey with dichotomous answers (yes/no) regarding their PAP experience (improved sleep, general discomfort, PAP related discomfort, mask discomfort, willingness to use PAP). Primary outcome was 30 day adherence (average time used per night, percent of nights used, percent of nights with >4 hours use). Results We enrolled 47 patients (68% male) with average age of 62.4 years, body mass index 32.6 kg/m2, and apnea-hypopnea index 27.8/hr. Patients answered an average of 3.4±1.3 survey questions favorably. The number of favorable answers correlated with percent of nights used and percent of nights with >4 hours use (P<0.05). Patients with improved sleep during PAP titration had a greater percent of nights with >4 hours use (82.4% vs 60.3%; P <0.05). In addition, successful titration during polysomnography (less than 5 events per hour) correlated with improved adherence and less leak after 30 days. Conclusion Initial PAP titration experience influences future PAP adherence. Although there was a correlation between answers on our pre-existing questionnaire and outcomes, some questions did not contribute much for this use. We believe a next step would be to develop questions that help predict future usage and better guide therapy. Support None