Proceedings of the American Thoracic Society
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Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome, are complex illnesses involving the interplay of both environmental (such as mechanical ventilation) and genetic factors. To understand better the underlying mechanisms of pathogenesis associated with ALI, we recently identified several candidate genes by global expression profiling in preclinical models of ALI and relevant single-nucleotide polymorphisms. We summarize here several strategies successfully used to identify novel ALI candidate genes and detail the validation of variants in these genes as contributing factors to ALI pathobiology, conclusions based on functional analyses, and specific genetic association studies conducted in ALI cohorts. Continued insights into ALI pathogenesis and identification of genetic variants, which confer ALI risk and severity, promise to reveal novel molecular therapeutic targets that can be translated into personalized treatments to reduce the very high, unacceptable mortality of this disorder.
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Familial pulmonary arterial hypertension (FPAH) was described 60 years ago, but real progress in understanding its origins and pathogenesis is just beginning. Germline mutations in bone morphogenetic protein receptor type 2 (BMPR2) are responsible for the disease in most families, and also in many sporadic cases of idiopathic PAH. Heritable PAH refers to patients with a positive family history, or with a responsible genetic mutation, and is an autosomal dominant disease that affects females disproportionately, may occur at any age, and is characterized by reduced penetrance and variable expressivity. ⋯ Furthermore, a linkage study recently identified modifier loci for BMPR2 clinical expression, which suggests an oligogenic model. Clinical testing for BMPR2 mutations is available for families with heritable and idiopathic PAH, and is an evolving model of personalized medicine. Variable age of onset and decreased penetrance confound genetic counseling, because the majority of carriers of a BMPR2 mutation will never develop PAH, but often transmit the risk to their progeny.
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Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of the lungs that increases in prevalence with advanced age. Recent evidence indicates that mutations in genes of two different biologic pathways lead to the common phenotype of familial pulmonary fibrosis (FPF) and sporadic IPF. Mutations in the genes encoding the lung surfactant proteins C and A2 (SFTPC and SFTPA2, respectively) cause increased endoplasmic reticulum stress in type II alveolar epithelial cells. ⋯ Short telomere lengths are found in patients with FPF and sporadic IPF without mutations in telomerase, suggesting that the biologic pathway of telomerase dysfunction provides a biologic explanation for the age-related prevalence of IPF. The molecular data of two seemingly unrelated biologic pathways-alveolar epithelial endoplasmic reticulum stress and telomerase dysfunction-are beginning to elucidate the pathogenesis of IPF. These results have potentially predictive and therapeutic value.
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The majority of cold and flulike illnesses are caused by human rhinoviruses (HRVs). Improved detection of HRV has shown that HRVs are also associated with more serious illness, such as exacerbation of asthma, wheezing illnesses in children, chronic obstructive pulmonary disease, cardiopulmonary disease, and fatal pneumonia in immune-compromised patients. HRV is a major cause of acute viral respiratory tract infections in hospitalized children and is among the leading causes of childhood mortality worldwide. ⋯ The enormous public health implications from those diseases far overshadow those of the common cold. This article provides an overview of the pathogenesis of rhinovirus infection in the upper airways. Most research has been done in young healthy adults with self-limiting experimental and natural rhinovirus infections, and this may set the stage for understanding rhinovirus infections in the ear, sinus, and lower airways.
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Review
Chlorine gas inhalation: human clinical evidence of toxicity and experience in animal models.
Humans can come into contact with chlorine gas during short-term, high-level exposures due to traffic or rail accidents, spills, or other disasters. By contrast, workplace and public (swimming pools, etc.) exposures are more frequently long-term, low-level exposures, occasionally punctuated by unintentional transient increases. Acute exposures can result in symptoms of acute airway obstruction including wheezing, cough, chest tightness, and/or dyspnea. ⋯ Early epithelial injury, airways hyperresponsiveness, and airway remodeling, likely diminishing over time, have been shown. As in humans, ALI/ARDS can occur, becoming more likely when the upper airways are bypassed. Inhalation models of chlorine toxicity provide unique opportunities for testing potential pharmacologic rescue agents.