IRAK-M Regulates Monocyte Trafficking to the Lungs in Response to Bleomycin Challenge.

Idiopathic pulmonary fibrosis is a deadly disease characterized by excessive extracellular matrix deposition in the lungs, resulting in decreased pulmonary function. Although epithelial cells and fibroblasts have long been the focus of idiopathic pulmonary fibrosis research, the role of various subpopulations of macrophages in promoting a fibrotic response is an emerging target. Healthy lungs are composed of two macrophage populations, tissue-resident alveolar macrophages and interstitial macrophages, which help to maintain homeostasis. After injury, tissue-resident alveolar macrophages are depleted, and monocytes from the bone marrow (BM) traffic to the lungs along a CCL2/CCR2 axis and differentiate into monocyte-derived alveolar macrophages (Mo-AMs), which is a cell population implicated in murine models of pulmonary fibrosis. In this study, we sought to determine how IL-1R-associated kinase-M (IRAK-M), a negative regulator of TLR signaling, modulates monocyte trafficking into the lungs in response to bleomycin. Our data indicate that after bleomycin challenge, mice lacking IRAK-M have decreased monocyte trafficking and reduced Mo-AMs in their lungs. Although IRAK-M expression did not regulate differences in chemokines, cytokines, or adhesion molecules associated with monocyte recruitment, IRAK-M was necessary for CCR2 upregulation following bleomycin challenge. This finding prompted us to develop a competitive BM chimera model, which demonstrated that expression of BM-derived IRAK-M was necessary for monocyte trafficking into the lung and for subsequent enhanced collagen deposition. These data indicate that IRAK-M regulates monocyte trafficking by increasing the expression of CCR2, resulting in enhanced monocyte translocation into the lung, Mo-AM differentiation, and development of pulmonary fibrosis.

Parenteral Prostanoid Use at a Tertiary Referral Center: A Retrospective Cohort Study.

BACKGROUND: Evidence-based guidelines recommend the use of parenteral prostaglandin (PP) therapy in patients with advanced pulmonary arterial hypertension (PAH). Despite this, many patients with PAH die without PP therapy. We sought to examine the frequency of PP use at a large referral center and characterize patients with PAH who died without receiving PP. METHODS: We conducted a single-center retrospective cohort analysis of consecutive patients with PAH between 2008 and 2012. Clinical data and cause of death were compared between patients with PAH treated with PP (PAH-PP) and those who were not but were not documented as poor PP candidates (PAH-nonPP). RESULTS: Of the 101 patients who received a diagnosis of PAH and died, 61 received PP therapy. Of the 40 patients not treated with PP, 10 did not have documented evaluations for PP therapy (PAH-nonPP) whereas 30 were not considered candidates or refused PP therapy. Compared with PAH-PP, PAH-nonPP had a longer 6-min walk distance, had a longer duration between time of diagnosis and date of worse functional class visit, were less likely to be diagnosed as functional class IV, and had significantly lower right atrial pressure. None of the PAH-nonPP died of progressive PAH. CONCLUSIONS: We found that most patients who die with PAH are evaluated for PP therapy at a large referral center and the small minority of PAH-nonPP tended to have less severe disease and die of non-PAH-related causes. Our data suggest that at large pulmonary hypertension (PH) centers, the vast majority of patients who are appropriate candidates receive PP therapy.