Neutrophil unsaturated fatty acid release by GM-CSF is impaired in cystic fibrosis

Dysregulated inflammation in cystic fibrosis (CF) is attributed to an altered production of inflammatory mediators derived from polyunsaturated lipids. In comparison to the arachidonic acid (AA) cascade, little is known about the modulation of docosahexaenoic acid (DHA) membrane release. We compared data on neutrophil DHA- and AA- release from both control (CT) and patients with CF using [3H]AA or [14C]DHA as a markers for, respectively, AA and DHA- release. Granulocyte-macrophage-colony stimulating factor stimulated DHA release from CT, but not CF, neutrophils. Comparison showed that both [14C]DHA and [3H]AA liberated after stimulation was higher in CT than in CF neutrophils. Since bioactive mediators derived from DHA are resolving factors and those derived from AA are both pro- and anti- inflammatory, these results suggest that CF is associated with a reduction of the release of PUFA-precursors of lipooxygenated resolving mediators. This leads to the hypothesis that defects in the resolving factors production could contribute to the inflammatory dysregulated processes in CF. Furthermore, the methodology used may help to improve knowledge on the regulation and resolution of inflammation

Impact of different chemotherapy regimens on intestinal mucosal injury assessed with bedside ultrasound: a study in 213 AML patients

IntroductionNeutropenic enterocolitis (NEC) is a life-threatening complication reported in patients with acute myeloid leukemia (AML) following chemotherapy (CHT). Intensive induction and consolidation CHT may damage intestinal mucosa leading to a NEC episode (NECe). NEC reported mortality may be up to 30-60%. Early US-guided bed-side diagnosis and prompt treatment may substantially improve the survival. An emerging worldwide concern is the intestinal colonization by multi-drug-resistant bacteria especially when patients are exposed to chemotherapy regimens potentially correlated to mucosal damage. MethodsIn our study we prospectively enrolled all AML patients admitted in our leukemia unit to receive intensive induction and consolidation chemotherapy and experiencing chemotherapy-induced-neutropenia (CHTN). Results and discussionOverall, we enrolled N=213 patients from 2007 to March 2023. We recorded N=465 CHTN, and N=42 NECe (9.0% incidence). The aim of our study was to assess which chemotherapy regimens are more associated with NEC. We found that ALM1310, followed by 7 + 3 (daunorubicin), 7 + 3 (idarubicin), 5 + 3 + 3 (cytarabine, etoposide, idarubicin), and AML1310 (consolidation) were associated with a statistically higher incidence of NEC. We did not detect NEC episodes in patients treated with CPX-351, 5 + 2 (cytarabine, idarubicine), and high-dose cytarabine. Thus, we found that cytarabine could determine mucosal damage when associated with an anthracycline but not if delivered either alone or as dual-drug liposomal encapsulation of daunorubicin/cytarabine. We also describe NEC mortality, symptoms at diagnosis, intestinal sites involvement, and prognostic significance of bowel wall thickening

Neutrophil generation of inflammatory precursors is not modulated by docosahexaenoic acid

It is believed that correction of membrane fatty acid deficiency in cystic fibrosis (CF) downregulates the synthesis of proinflammatory mediators. We tested the hypothesis that an increase of the proportion of docosahexaenoic acid (DHA) in the membrane in vitro changes the neutrophil response to Pseudomonas aeruginosa lipopolysaccharide (LPS). Treatment with DHA increased the secretion of interleukin(IL)-1|*alpha*| by CF neutrophils, but the secretion of other cytokines, CD11b expression, and arachidonic acid (AA) release were not affected either in CF or control (CT) neutrophils. Both with and without DHA, only one out of eight CF neutrophils responded to LPS with an increase of released AA, while five out of seven CT cells released more AA (CF vs. CT P < 0.05 by Fisher test). These results indicate that in neutrophils the beneficial effects of DHA on immune response are not directly related to the generation of proinflammatory precursors, and suggest that in CF the lower neutrophil AA generation in response to activation could cause insufficient production of lipid mediators involved in the resolution of lung inflammation

What's new in the treatment of neonatal shock

Shock is a clinical disorder that challenges caregivers in the neonatal intensive care unit. The predominant cause of shock in neonates is sepsis. This article provides an overview of the current treatment of septic shock with particular emphasis on newer vasoactive drugs (milrinone, levosimendan and vasopressin) to support cardiovascular dysfunction

Urokinase plasminogen activator and TGF-beta production in immunosuppressed patients with and without P. Jiroveci infection.

Macrophages play a pivotal role in a host’s defence against pulmonary infections. Macrophage functions are impaired in immunosuppressed (IS) patients, regardless of whether they are HIV-positive (HIV+) or –negative (HIV). Several studies have indicated that urokinase plasminogen activator (uPA) and transforming growth factor b (TGF-b) are important factors in a host’s defence against pulmonary pathogens. We measured uPA and TGF-b activity in unstimulated peripheral blood monocytes (PBM) of both HIV-infected and non-infected IS patients with or without Pneumocystis jiroveci (formerly carinii) pneumonia (PCP). As previously found in alveolar macrophages (AMs), the majority of uPA activity was found in cell lysates. The highest values of uPA activity were found in control subjects. All the patients displayed a decreased production of uPA, irrespective of HIV infection. Similarly, active TGF-b was higher in control subjects than in HIV+ and IS patients. The presence of P. jiroveci infection further lowered uPA and TGF-b activity. Decreased TGF-b activation might be a consequence of lower uPA production, which may, in turn, influence virus replication, since it has been demonstrated that TGF-b can suppress human HIV expression in monocytes/macrophages. Further studies are warranted to elucidate whether the decrease in uPA and TGF-b activity impairs a host’s defence against P. jiroveci infection

Lung transplantation for cystic fibrosis in Italy

Lung transplantation (LT) is the only effective form of therapy for cystic fibrosis (CF) associated with end-stage pulmonary failure. In Italy, the management of CF is regulated by national law, which has instituted regional centers for care and follow-up of all CF patients. LT has been performed since 1992 in only nine LT certified centers. The structured national organization has led to a unified database for LT for CF. As of December 2006, 197 bilateral LT (96 male and 94 female patients; 7 retransplants) have been performed. Of these, four had also liver or heart and liver transplantation, and three are long-term survivors. Overall median survival is 7 years. Mean age at transplantation is 26.5 years, and the mortality on the waiting list is 33.6%. Patients listed for transplant either received a suitable donor within a mean of 10 months or died within a mean of 5.5 months. The most frequent cause of death is bronchiolitis obliterans syndrome (BOS). Our nationwide database indicates the excellent results obtained by LT in FC. Still, mortality on the waiting list remains a challenge and long-term outcome is limited by BOS

Neutrophil generation of inflammatory precursors is not modulated by docosahexaenoic acid

It is believed that correction of membrane fatty acid deficiency in cystic fibrosis (CF) downregulates the synthesis of proinflammatory mediators. We tested the hypothesis that an increase of the proportion of docosahexaenoic acid (DHA) in the membrane in vitro changes the neutrophil response to Pseudomonas aeruginosa lipopolysaccharide (LPS). Treatment with DHA increased the secretion of interleukin(IL)-1|*alpha*| by CF neutrophils, but the secretion of other cytokines, CD11b expression, and arachidonic acid (AA) release were not affected either in CF or control (CT) neutrophils. Both with and without DHA, only one out of eight CF neutrophils responded to LPS with an increase of released AA, while five out of seven CT cells released more AA (CF vs. CT P < 0.05 by Fisher test). These results indicate that in neutrophils the beneficial effects of DHA on immune response are not directly related to the generation of proinflammatory precursors, and suggest that in CF the lower neutrophil AA generation in response to activation could cause insufficient production of lipid mediators involved in the resolution of lung inflammation