Several clinical trials have recently targeted specific pathways implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, IPF remains plagued by a median survival of 3 yrs and emphasises the need for further research with new insights and perspectives. The prevailing pathogenic hypotheses assume that either an inflammatory process or an independent epithelial/fibroblastic disorder may propagate the disease process. Based on knowledge developed with considerable scientific evidence, we provide our perspectives with an alternative point of view that IPF be considered as a neoproliferative disorder of the lung. Genetic alterations, response to growth and inhibitory signals, resistance to apoptosis, myofibroblast origin and behaviour, altered cellular communications, and intracellular signalling pathways are all fundamental pathogenic hallmarks of both IPF and cancer. The concept of IPF as a lethal malignant disorder of the lung might extend beyond the pathogenic link between these two diseases and disclose new pathogenic mechanisms leading to novel therapeutic options, adopted from cancer biology. Moreover, this vision might dawn the awareness of the public, political and scientific community of this devastating disease from an angle different from the current perception and provoke new ideas and studies to get a better understanding to control the otherwise relentless progressive disease.

Treatment guidelines recommend the regular use of inhaled corticosteroids for patients with mild persistent asthma. We investigated whether the symptom-driven use of a combination of beclomethasone dipropionate and albuterol (also known as salbutamol) in a single inhaler would be as effective as the regular use of inhaled beclomethasone and superior to the as-needed use of inhaled albuterol.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of this fatal disorder remains unclear, transforming growth factor-β (TGF-β)-induced differentiation and proliferation of myofibroblasts is recognized as a primary event. The molecular pathways involved in TGF-β signalling are generally Smad-dependent yet Smad-independent pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), have been recently proposed. In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the PI3K/Akt pathway in two critical stages of the fibrotic process induced by TGF-β: fibroblast proliferation and differentiation into myofibroblasts. Here we show that the pan-inhibitor of PI3Ks LY294002 is able to abrogate the TGF-β-induced increase in cell proliferation, in α- smooth muscle actin expression and in collagen production besides inhibiting Akt phosphorylation, thus demonstrating the centrality of the PI3K/Akt pathway in lung fibroblast proliferation and differentiation. Moreover, for the first time we show that PI3K p110δ and p110γ are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p110α and β. Finally, results obtained with both selective inhibitors and gene knocking-down experiments demonstrate a major role of p110γ and p110α in both TGF-β-induced fibroblast proliferation and differentiation. This finding suggests that specific PI3K isoforms can be pharmacological targets in IPF.

Thiazolidinedione rosiglitazone and 15-deoxy-Δ^12,14-prostaglandin J₂(15d-PGJ₂), are two peroxisome proliferator-activated receptor (PPAR)-γ ligands. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ₂on the lung injury caused by bleomycin administration.Mice subjected to intratracheal administration of bleomycin developed significant lung injury. An increase in immunoreactivity to nitrotyrosine, poly(ADP ribose) polymerase (PARP) and inducible nitric oxide synthase as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated mice.Administration of the two PPAR-γ agonists rosiglitazone (10 mg·kg⁻¹i.p.) and 15d-PGJ₂(30 µg·kg⁻¹i.p.) significantly reduced the: 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) oedema formation, and 5) histological evidence of lung injury. Administration of rosiglitazone and 15d-PGJ₂also markedly reduced the nitrotyrosine, PARP and inducible nitric oxide synthase formation. In addition, treatment with the PPAR-γ antagonist bisphenol A diglycidyl ether (1 mg·kg⁻¹i.p. 30 min before the rosiglitazone or 15d-PGJ₂) significantly antagonised the effect of the two PPAR-γ agonists.These results demonstrate that the two peroxisome proliferator-activated receptor-γ agonists, rosiglitazone and 15-deoxy-Δ^12,14-prostaglandin J₂, significantly reduce lung injury induced by bleomycin in mice.

Asthma is one of the most common non-communicable respiratory diseases, affecting about 6% of the general population. Severe asthma, even if afflicts a minority of asthmatics, drives the majority of costs of the disease. The aim of this study is to create a pharmacoeconomic model to predict the costs of corticosteroid-related adverse events in severe asthmatics and applying it to the first published epidemiologic data from the Severe Asthma Network in Italy (SANI) registry. The analysis was conducted from the perspective of the Italian National Healthcare System (INHS). Model inputs, derived from literature, included: asthma epidemiology data, frequency of adverse events, percentage of severe asthma treated with OCS and adverse event cost (Diagnosis-Related Group (DRG) national tariffs). We estimated costs per different patient groups: non-asthma controls, mild/moderate and severe asthmatics. Final results report estimated direct cost per patient and total direct cost for overall target population, showing economic impact related to corticosteroid complication. Based on epidemiological data input, in Italy, asthmatic subjects resulted about 3,999,600, of which 199,980 with severe asthma. The number of patients with severe asthma OCS-treated was estimated at 123,988. Compared to the non-asthma control cohort and to that with moderate asthma annual cost per severe asthmatic patient resulted respectively about €892 and €606 higher, showing a corticosteroids shadow cost ranging from 45% to 30%.Applying the cost per patient to the target population identified for Italy, the budget impact model estimated a total annual cost related to OCS-related adverse events of €242.7 million for severe asthmatics. In respect with non-asthmatic and moderate population, an incremental expenditure of about € 110.6 million and €75.2, respectively, were shown. Our study provides the first estimates of additional healthcare costs related to corticosteroid induced adverse events in severe asthma patient. Budget impact model results highlighted the relevant economic impact of OCS-related adverse events in severe asthma patients. The future extrapolation of additional data from SANI registry will support the development of a model to investigate the role of corticosteroids sparing drugs.