American journal of physiology. Lung cellular and molecular physiology
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Aug 2013
Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells.
Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases of heritable pulmonary arterial hypertension (PAH). Loss of BMP signaling promotes pulmonary vascular remodeling via modulation of pulmonary artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1-4) are major downstream transcriptional targets of BMP signaling. ⋯ Lipopolysaccharide further reduced Id3 expression in mutant PASMCs. In conclusion, Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in PASMCs. Loss of BMPR-II function reduces the induction of Id genes in PASMCs, Id1, and Id3 regulate the proliferation of PASMCs via cell cycle inhibition, an effect that may be exacerbated by inflammatory stimuli.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jul 2013
ReviewAdapting global influenza management strategies to address emerging viruses.
Death by respiratory complications from influenza infections continues to be a major global health concern. Antiviral drugs are widely available for therapy and prophylaxis, but viral mutations have resulted in resistance that threatens to reduce the long-term utility of approved antivirals. Vaccination is the best method for controlling influenza, but vaccine strategies are blunted by virus antigenic drift and shift. ⋯ Recently, a novel H7N9 avian influenza virus with potential to become a pandemic strain emerged in China and was transmitted from animals to humans with a demonstrated >20% mortality rate. Sporadic outbreaks of highly lethal avian virus strains have already increased public awareness and altered annual vaccine production strategies to prevent the natural adaption of this virus to human-to-human transmission. Additional strategies for combating influenza include advancement of new antivirals for unexploited viral or host cellular targets; novel adjuvants and alternate vaccine delivery systems; and development of universal protein, DNA, or multivalent vaccines designed to increase immune responsiveness and enhance public health response times.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jul 2013
Neu-164 and Neu-107, two novel antioxidant and anti-myeloperoxidase compounds, inhibit acute cigarette smoke-induced lung inflammation.
Cigarette smoke is a profound proinflammatory stimulus that causes acute lung inflammation and chronic lung disease, including chronic obstructive pulmonary disease (COPD, emphysema, and chronic bronchitis), via a variety of mechanisms, including oxidative stress. Cigarette smoke contains high levels of free radicals, whereas inflammatory cells, including macrophages and neutrophils, express enzymes, including NADPH oxidase, nitric oxide synthase, and myeloperoxidase, that generate reactive oxygen species in situ and contribute to inflammation and tissue damage. Neu-164 and Neu-107 are small-molecule inhibitors of myeloperoxidase, as well as potent antioxidants. ⋯ Upregulation of endogenous antioxidant genes was dampened. Neu-164 and Neu-107 inhibit acute cigarette smoke-induced inflammation by scavenging reactive oxygen species in cigarette smoke and by inhibiting further oxidative stress caused by inflammatory cells. These compounds may have promise in preventing or treating lung disease associated with chronic smoke exposure, including COPD.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jun 2013
Impairment of autophagy decreases ventilator-induced lung injury by blockade of the NF-κB pathway.
Excessive lung stretch triggers lung inflammation by activation of the NF-κB pathway. This route can be modulated by autophagy, an intracellular proteolytic system. Our objective was to study the impact of the absence of autophagy in a model of ventilator-induced lung injury. ⋯ High-pressure ventilation partially restored the autophagic response in Atg4b-/- mice and abolished the differences between genotypes. In conclusion, impairment of autophagy results in an ameliorated inflammatory response to mechanical ventilation and decreases lung injury. The accumulation of ubiquitinated IκB may be responsible for this effect.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jun 2013
The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat.
Allergen challenges induce airway hyperresponsiveness (AHR) and increased airway smooth muscle (ASM) mass in the sensitized rat. Whether the remodeled ASM changes its phenotype is uncertain. We examined, in sensitized Brown Norway rats, the effects of multiple ovalbumin (Ova) challenges on ASM remodeling and phenotype and the role of the epidermal growth factor receptor (EGFR) in these processes. ⋯ Epithelial gene expression of EGFR, HB-EGF, matrix metalloproteinase (MMP)-9, Gro-α, and transforming growth factor-β was unaffected by Ova challenges. We conclude that EGFR drives remodeling of ASM, which results from repeated Ova challenge. Furthermore, the latter results in excessive small airway and, to a lesser degree, large airway narrowing to methacholine, and large airway gene expression of contractile protein is conserved.