PDE4 inhibition drives resolution of neutrophilic inflammation by inducing apoptosis in a PKA-PI3K/Akt-dependent and NF-kappaB-independent manner.

PDE4 inhibitors are effective anti-inflammatory drugs whose effects and putative mechanisms on resolution of inflammation and neutrophil apoptosis in vivo are still unclear. Here, we examined the effects of specific PDE4 inhibition on the resolution of neutrophilic inflammation in the pleural cavity of LPS-challenged mice. LPS induced neutrophil recruitment that was increased at 4 h, peaked at 8-24 h, and declined thereafter. Such an event in the pleural cavity was preceded by increased levels of KC and MIP-2 at 1 and 2 h. Treatment with the PDE4 inhibitor rolipram, at 4 h after LPS administration, decreased the number of neutrophils and increased the percentage of apoptotic cells in the pleural cavity in a PKA-dependent manner. Conversely, delayed treatment with a CXCR2 antagonist failed to prevent neutrophil recruitment. Forskolin and db-cAMP also decreased the number of neutrophils and increased apoptosis in the pleural cavity. The proapoptotic effect of rolipram was associated with decreased levels of the prosurvival protein Mcl-1 and increased caspase-3 cleavage. The pan-caspase inhibitor zVAD-fmk prevented rolipram-induced resolution of inflammation. LPS resulted in a time-dependent activation of Akt, which was blocked by treatment with rolipram or PI3K and Akt inhibitors, and PI3K and Akt inhibitors also enhanced apoptosis and promoted neutrophil clearance. Although LPS induced NF-kappaB activation, which was blocked by rolipram, NF-kappaB inhibitors did not promote resolution of neutrophil accumulation in this model. In conclusion, our data show that PDE4 inhibition resolves neutrophilic inflammation by promoting caspase-dependent apoptosis of inflammatory cells by targeting a PKA/PI3K/Akt-dependent survival pathway.

Cyclic AMP enhances resolution of allergic pleurisy by promoting inflammatory cell apoptosis via inhibition of PI3K/Akt and NF-kappaB.

Selective and timely induction of apoptosis is an effective means of resolving inflammation. The effects and putative mechanisms by which cyclic AMP (cAMP) modulates leukocyte apoptosis in vivo are still unclear. The present study aims at identifying intracellular pathways underlying the ability of cAMP elevating agents to resolve eosinophilic inflammation in a model of allergic pleurisy in mice. Ovalbumin (OVA) challenge of immunized mice induced eosinophil recruitment that peaked at 24h and persisted till 48h. Treatment with the PDE4 inhibitor rolipram, cAMP mimetic db-cAMP or adenylate cyclase activator forskolin, at 24h after antigen-challenge resulted in profound resolution of eosinophilic inflammation, without a decrease of mononuclear cell numbers. There was a concomitant increase in number of apoptotic cells in the pleural cavity. The effects of rolipram and db-cAMP were inhibited by the PKA inhibitor H89. Inhibition of PI3K/Akt or NF-kappaB induced resolution of inflammation that was associated with increased apoptosis. OVA-challenge resulted in a time-dependent activation of Akt and NF-kappaB, which was blocked by treatment with rolipram or PI3K/Akt pathway inhibitors. Thus, cAMP elevating agents resolve established eosinophilic inflammation by inducing leukocyte apoptosis. Mechanistically, the actions of cAMP are dependent on PKA and target a PI3K/Akt-dependent NF-kappaB survival pathway.

A study of continuing medical education in Jamaica: report of the results of a postal survey of the doctors in the island

Continuing Medical Education is defined by the World Health Organisation as the training that an individual physician undertakes after the end of his basic medical education, and where applicable, after the end of any additional education for a career as a generalist or a specialist - training to improve his competence as a practitioner (not with a view to gaining a new qualifying diploma or license). Continuing Medical Education, hereinafter referred to as CME, has been a growth industry in practically all developed nations for at least the last thirty years. While much is known about the theory and practice of CME in other countries little has been documented in Jamaica and the Caribbean. Organised CME activities, such as clinical meetings or symposia, have appeared to be poorly attended, with the impression that doctors generally are little interested in CME. Attendance at these meetings are usually in the range of 40-200 doctors out of an estimated total in excess of 900. It was felt that this was not a true reflection of doctors' interest in CME and the present study was undertaken to evaluate current opinion on CME and analyse the practice of CME among doctors in the island. The study took the form of a postal questionnaire mailed to all doctors (875), excluding interns, in January 1987, and again in February 1987. These responses provide heretofore undocumented information on CME in Jamaica, and are presented along with some recommendations for future planning of CME. Analysis of the results confirm that 67 percent of doctors in the island are to be found in the corporate area, and additionally, that 67 percent are male. Those engaged in full-time clinical general practice constituted 44 percent of the respondents, 32 percent were full-time specialists, and, 23 percent practised in a speciality, or were in residency training, as well as being engaged in part-time general practice. The respondents included 50 percent of the membership of the Medical Association of Jamaica, 54 percent of the membership of the Association of General Practitioners of Jamaica, and 38 percent of the membership of the Paediatric Association of Jamaica. 75 percent of general practitioner respondents attended between one to six CME meetings in the period under study, with 13 percent attending more than six. These figures were similar for specialists and part-time general practitioners. This study also showed that practitioners from rural addresses attend just as many meetings as corporate area doctors. Reading was shown to be the most popular form of personal CME, with only 4 percent of general practitoners reporting no reading at all, a figure equal to that reported by specialists. Little use of audio cassettes, video, and other less traditional forms of CME was reported by more than 80 percent of doctors in all categories. In response to the question of availability of CME, 38 percent replied that availability was "More than adequate" or "Adequate". 19 percent thought it was "barely adequate"; and, 43 percent thought it was "Inadequate", or "Grossly inadequate". Not surprisingly, two thirds of those who made the latter responses were from rural addresses, while only a third of their corporate area colleagues shared this view. Other important results include the overwhelming opinion that CME is "Absolutely essential". When asked to give their opinion of CME, 88 percent of reponders replied that CME was "Absolutely essential"; a further 8 percent thought it was "Desirable, but not essential"; while only 2 percent thought it was "Optional". No respondents thought CME was unnecessary. In answer to the question, "At present a medical degree and registration are the only requirements for you to practice for the rest of your life. Should this remain so?" 69 percent of respondents said "No"; while 30 percent said "Yes". Of note, is the fact that, 65 percent were also in favour of periodic recertification as opposed to 33 percent who were not. Based on these findings it is felt that the profession in Jamaica is receptive to the principles of CME as defined above and is ready to accept the responsibility of recertification. It is now the duty of the profession to develop the resources to achieve these ideals. To these ends certain recommendations are presented (AU)