The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm

Lars Heslet1, Christiane Bay2, Steen Nepper-Christensen31Serendex ApS, Gentofte, Denmark; 2University of Copenhagen, Medical Faculty, Copenhagen, Denmark; 3Department of Head and Neck Surgery, Otorhinolaryngology, Køge Hospital, DenmarkBackground: Patients with cystic fibrosis (CF) experience recurrent infections and develop chronically infected lungs, which initiates an altered immunological alveolar environment. End-stage pulmonary dysfunction is a result of a long sequence of complex events in CF, progressing to alveolar macrophage dysfunction via a T-helper 2 (TH2) dominated alveolar inflammation with CD20 T-cell activation, induced by the chronic infection and showing a poor prognosis. There is great potential for treatment in transforming the TH2 into the more favorable T-helper 1 (TH1) response.Methods: Current literature in the PubMed database and other sources was reviewed in order to evaluate aspects of the innate alveolar host defense mechanisms and the potential impact on the immunoinflammatory response of inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with CF.Results: It seems that the cellular host defense, (ie, the alveolar macrophage and neutrocyte function) and the inhaled GM-CSF interact in such a way that the so-called tolerant alveolar environment dominated by the TH2 response may be transformed into an active TH1 state with a normal pulmonary host defense. The shift of the TH2 to the TH1 subset dominated by specific and unspecific antibodies may be achieved after the inhalation of GM-CSF. A clinical report has shown promising results with inhalation of GM-CSF in a chronically-infected CF patient treated with several antibacterial and antifungal agents. Inhaled GM-CSF transformed the tolerance toward the Gram-negative infection reflected by the so-called TH2 subset into the more acute TH1 response characterized by recruitment of the T-cells CD8 and CD16, a condition related to better-preserved lung function. This indicated a transformation from a state of passive bacterial tolerance toward the Gram-negative infecting and colonizing bacteria. This GM-CSF effect cannot be achieved by administering the drug via the IV route because the drug is water-soluble and too large to penetrate the alveolocapillary membrane.Conclusions: Inhalation of GM-CSF seems to be a novel way to positively modulate the alveolar environment toward an altered immunological state, reflected by a positive change in the pattern of surrogate markers, related to better preservation of pulmonary function and thus improved outcomes in CF patients. It is suggested that future studies examining standard endpoint variables such as number of infections and amount of antibiotics used should be supplemented by surrogate markers, to reveal any positive cellular and cytokine responses reflecting changes in the alveolar compartment after GM-CSF inhalation. The immunological alveolar environment should be monitored by a specific pattern of surrogate markers. Continued research is clearly indicated and the role of inhaled GM-CSF in modulating pulmonary host defense in CF patients should be investigated in a large study.Keywords: cystic fibrosis, granulocyte-macrophage colony-stimulating factor, TH1 response, TH2 subset, surrogate marker

Left ventricular hypertrophy is associated with increased infarct size and decreased myocardial salvage in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

Background Approximately one third of patients with ST‐segment elevation myocardial infarction (STEMI) have left ventricular hypertrophy (LVH), which is associated with impaired outcome. However, the causal association between LVH and outcome in STEMI is unknown. We evaluated the association between LVH and: myocardial infarct size, area at risk, myocardial salvage, microvascular obstruction, left ventricular (LV) function (all determined by cardiac magnetic resonance [CMR]), and all‐cause mortality and readmission for heart failure in STEMI patients treated with primary percutaneous coronary intervention. Methods and Results In this substudy of the DANAMI‐3 trial, 764 patients underwent CMR. LVH was defined by CMR and considered present if LV mass exceeded 77 (men) and 67 g/m 2 (women). One hundred seventy‐eight patients (24%) had LVH. LVH was associated with a larger final infarct size (15% [interquartile range {IQR}, 10–21] vs 9% [IQR, 3–17]; P &lt;0.001) and smaller final myocardial salvage index (0.6 [IQR, 0.5–0.7] vs 0.7 [IQR, 0.5–0.9]; P &lt;0.001). The LVH group had a higher incidence of microvascular obstruction (66% vs 45%; P &lt;0.001) and lower final LV ejection fraction (LVEF; 53% [IQR, 47–60] vs 61% [IQR, 55–65]; P &lt;0.001). In a Cox regression analysis, LVH was associated with a higher risk of all‐cause mortality and readmission for heart failure (hazard ratio 2.59 [95% CI, 1.38–4.90], P =0.003). The results remained statistically significant in multivariable models. Conclusions LVH is independently associated with larger infarct size, less myocardial salvage, higher incidence of microvascular obstruction, lower LVEF, and a higher risk of all‐cause mortality and incidence of heart failure in STEMI patients treated with primary percutaneous coronary intervention. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01435408. </jats:sec

Festskrift til en idéhistorisk opdrager – og opdager : Til Jens Erik Kristensen efter 40 år i universitetets tjeneste

De talrige og mangeartede bidrag i dette festskrift til Jens Erik Kristensen tegner både et billede af en usædvanlig afholdt og alsidig idehistoriker, forsker og underviser og bærer samtidig vidnesbyrd om genkommende temaer, analytiske mønstre og kritisk-teoretiske tilgange, som har fulgt Jens Erik Kristensen siden studietiden i 1970erne og de første ansættelser på Aarhus Universitet i starten af 1980erne. Festskriftet indeholder bidrag fra kolleger og samarbejdspartnere gennem en menneskealder. Tekster, der handler om Jens Erik Kristensen og tekster til Jens Erik Kristensen. Om de spor han krydsede, og de spor han satte sig. De beretter på den ene side om, hvad Jens Erik Kristensen nu forlader ligesom det på den anden side er tydeligt, at en særegen og markant forsker og underviser efterlader sig et tomrum på sit alma mater og vigtigere: i de skiftende miljøer hvor han har udlevet sine akademiske idealer. Bidragenes genremæssige og stilistiske forskellighed afspejler også Kristensens vidtforgrenede interesser og forbindelser, ligesom de åbenlyst er skrevet som en cadeau og en tak – selvsagt uden panegyrik – til en akademisk figur, der aldrig har søgt spotlyset, men tværtom bevaret en spirende nysgerrighed og generøst skrevet og samarbejdet med et utal af forskellige kolleger og på tværs af discipliner og faggrænser