Maria Molina-Molina

Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis.

Earlier work from this laboratory showed that local generation of angiotensin (ANG) II is required for the pathogenesis of experimental pulmonary fibrosis and that ANG peptides are expressed robustly in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Angiotensin converting enzyme-2 (ACE-2) degrades the octapeptide ANG II to form the heptapeptide ANG1-7 and thereby limits ANG II accumulation. On this basis, we hypothesized that ACE-2 would be protective against experimental lung fibrogenesis and might be downregulated in human and experimental lung fibrosis. In lung biopsy specimens from patients with IPF, ACE-2 mRNA and enzyme activity were decreased by 92% (P<0.01) and 74% (P<0.05), respectively. ACE-2 mRNA and activity were also decreased similarly in the lungs of bleomycin-treated rats and C57-BL6 mice. In mice exposed to low doses of bleomycin, lung collagen accumulation was enhanced by intratracheal administration of either ACE-2-specific small interfering RNAs (siRNAs) or the peptide DX(600), a competitive inhibitor of ACE-2 (P<0.05). Administration of either ACE-2 siRNA or DX(600) significantly increased the ANG II content of mouse lung tissue above the level induced by bleomycin alone. Coadministration of the ANG II receptor antagonist saralasin blocked the DX(600)-induced increase in lung collagen. Moreover, purified recombinant human ACE-2, delivered to mice systemically by osmotic minipump, attenuated bleomycin-induced lung collagen accumulation. Together, these data show that ACE-2 mRNA and activity are severely downregulated in both human and experimental lung fibrosis and suggest that ACE-2 protects against lung fibrogenesis by limiting the local accumulation of the profibrotic peptide ANG II.

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events.

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis

Background: The angiotensin system has a role in the pathogenesis of pulmonary fibrosis. This study examines the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in bleomycin induced lung fibrosis and its possible implication in the regulation of prostaglandin E2 (PGE2) synthesis and cyclooxygenase-2 (COX-2) expression. Methods: Rats were given a single intratracheal instillation of bleomycin (2.5 U/kg). Losartan (50 mg/kg/day) was administrated orally starting one day before induction of lung fibrosis and continuing to the conclusion of each experiment. Results: Losartan reduced the inflammation induced by bleomycin, as indicated by lower myeloperoxidase activity and protein content in the bronchoalveolar lavage fluid. Collagen deposition induced by bleomycin was inhibited by losartan, as shown by a reduction in the hydroxyproline content and the amelioration of morphological changes. PGE2 levels were lower in fibrotic lungs than in normal lungs. Losartan significantly increased PGE2 levels at both 3 and 15 days. A reduction in COX-2 expression by bleomycin was seen at 3 days which was relieved by losartan. Conclusions: The antifibrotic effect of losartan appears to be mediated by its ability to stimulate the production of PGE2. Losartan, which is already widely used clinically, could be assessed as a new treatment in lung fibrosis.

ANGIOTENSIN SIGNALLING IN PULMONARY FIBROSIS

A large body of evidence demonstrates that angiotensin II and angiotensin receptors are required for the pathogenesis of experimental lung fibrosis. Angiotensin has a number of profibrotic effects on lung parenchymal cells that include the induction of growth factors for mesenchymal cells, extracellular matrix molecules, cytokines and increased motility of lung fibroblasts. Angiotensin is also proapoptotic for lung epithelial cells, and is synthesized by a local system (i.e., entirely within the lung tissue) after lung injury by a variety of agents of both xenobiotic and endogenous origins. Recent evidence shows that the counterregulatory molecule angiotensin 1-7, the product of the enzyme ACE-2, inhibits epithelial cell apoptosis and thus acts as an antifibrotic epithelial survival factor. This manuscript reviews the evidence supporting a role for angiotensin in lung fibrogenesis and discusses the signalling mechanisms underlying its action on lung parenchymal cells important in the pathogenesis of pulmonary fibrosis.

European IPF Patient Charter: unmet needs and a call to action for healthcare policymakers

Patient advocacy groups play an important role in supporting patients with chronic diseases and promoting better care. The aim of this patient–physician initiative was to gather perceptions from European idiopathic pulmonary fibrosis (IPF) patient advocacy groups regarding inequalities and unmet needs in IPF care, in order to develop a Patient Charter to advocate for better care. In total, 11 European patient advocacy groups were interviewed regarding the care of patients with IPF in their countries. Interview feedback was presented to a Working Group including patient advocacy group representatives and IPF specialists; key areas of agreement were developed into the European IPF Patient Charter. The interviews identified five key themes that fed into the final Charter: the need for improved diagnosis, treatment access, holistic care, disease awareness and palliative care. The final Charter was endorsed by patient advocacy groups and presented to 26 Members of the European Parliament in September 2014. It has received >8900 signatures to date. This patient–physician initiative highlights the inequalities and unmet needs in IPF care across Europe, and demonstrates how this insight can inform the development of a Patient Charter, designed as a call to action for healthcare policymakers to drive improvement in European IPF care. European IPF Patient Charter details unmet needs in IPF and presents a call to action for healthcare policymakers http://ow.ly/Td8rj

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case–control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37±0.7 mmHg (0.049±0.093 kPa) per month) compared to GA genotype (0.12±1 mmHg (0.016±0.133 kPa) per month) and GG genotype (0.2±0.6 mmHg (0.027±0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.

Características clínicas y pronóstico de los pacientes con fibrosis pulmonar que ingresan en cuidados intensivos por insuficiencia respiratoria. Análisis de 20 casos

Fundamento y objetivo: Diversos estudios indican que el pronostico global de los pacientes con fibrosis pulmonar que ingresan en unidades de cuidados intensivos (UCI) es muy malo. El objetivo de este trabajo fue investigar la evolucion y el pronostico de los pacientes con fibrosis pulmonar que requieren ingreso en cuidados intensivos por insuficiencia respiratoria aguda. Pacientes y metodo: Estudio observacional retrospectivo de serie de casos. Se evaluo a los pacientes con fibrosis pulmonar ingresados en la UCI de un hospital terciario entre enero de 1986 y junio de 2002. Se recogieron datos sobre el diagnostico de base, evolucion clinica y tratamiento, estudio funcional respiratorio, ingreso actual, abordaje clinico, ventilacion mecanica, comportamiento mecanico y gasometrico, dias de estancia y mortalidad. Resultados: Se incluyo a 20 pacientes, 14 con fibrosis pulmonar idiopatica y 6 con fibrosis asociada a colagenosis. El tiempo medio (DE) transcurrido desde el diagnostico de fibrosis hasta el ingreso en la UCI fue de 14 (20) meses. Todos presentaban insuficiencia respiratoria grave (PaO2/FiO2 < 200). La causa de la insuficiencia respiratoria se identifico en 8 casos (en 5 era una infeccion bacteriana y en 3 una infeccion fungica). En los 12 casos restantes (60%) no se identifico ningun agente causal. Durante el ingreso en la UCI 17 pacientes precisaron ventilacion mecanica; en los tres casos restantes se limito el esfuerzo terapeutico. Todos, sin excepcion, presentaron una mala evolucion, destacando la alta incidencia de hipoxemia refractaria (100%) e inestabilidad hemodinamica grave tras la intubacion (70%). Tanto la mortalidad asociada a la ventilacion mecanica como la mortalidad intrahospitalaria fueron del 100%. Conclusion: El desencadenante de la insuficiencia respiratoria y el deterioro clinico no son identificables en una proporcion significativa de pacientes a pesar de una aproximacion diagnostica sistematica. La ventilacion mecanica y las medidas de soporte vital agresivo no parecen ofrecer ningun beneficio a los pacientes con fibrosis pulmonar que ingresan en UCI por insuficiencia respiratoria.

Consumo máximo de oxígeno durante la prueba de marcha de 6 minutos en la enfermedad pulmonar intersticial difusa y en la hipertensión pulmonar

INTRODUCTION The six-minute walk test (6MWT) is widely used in evaluating diffuse interstitial lung disease (ILD) and pulmonary hypertension (PH). However, their physiological determining factors have not been well defined. OBJECTIVE To evaluate the physiological changes that occur in ILD and PH during the 6MWT, and compare them with the cardiopulmonary exercise test (CPET). MATERIAL AND METHODS Thirteen patients with ILD and 14 with PH were studied using the 6MWT and CPET on an ergometer cycle. The respiratory variables were recorded by means of telemetry during the 6MWT. RESULTS Oxygen consumption (VO(2)), respiratory and heart rate reached a plateau from minute 3 of the 6MWT in both diseases. The VO(2) did not differ from the peak value in the CPET (14+/-2 and 15+/-2 ml/kg/min, respectively, in ILD; 16+/-6 and 16+/-6 ml/kg/min, in PH). The arterial oxygen saturation decreased in both diseases, although it was more marked in ILD (-12+/-5%, p<0,01). The ventilatory equivalent for CO(2) (V(E)/VCO(2)) in PH during the 6MWT was strongly associated with functional class (FC) (85+/-14 in FC III-IV, 44+/-6 in FC I-II; p<0,001). CONCLUSIONS The 6MWT in ILD and PH behaves like a maximal effort test, with similar VO(2) to the CPET, demonstrating a limit in oxygen transport capacity. Monitoring using telemetry during the 6MWT may be useful for the clinical evaluation of patients with ILD or PH.

Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?

Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF.

Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of unknown aetiology and poor prognosis, characterized by altered tissue repair and fibrosis. The extracellular matrix (ECM) is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in IPF lungs.MethodsECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), categorized as chronic (cHP) and subacute (saHP), and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate tenascin-C (TNC) synthesis.ResultsA total of 20 ECM proteins were upregulated and 6 proteins downregulated in IPF. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs (IPF and cHP) compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from IPF patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and α-sma was induced by TGF-β1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased α-sma mRNA.ConclusionsThe difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung fibrosis. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.