Cellular Mechanisms of Pulmonary Dysfunction in an Animal Model of CIH
Introduction
Both chronic intermittent hypoxia (CIH) and particulate exposure can lead to lung injury and dysfunction. These exposures have been associated with neurocognitive and cardiovascular complications. This is a particular problem for individual’s exposed to World Trade Center (WTC) dust, who often suffer intermittent hypoxia because of obstructive sleep apnea. The current studies seek to understand how the interaction between WTC dust exposure and CIH can lead to lung injury and a loss of function. Following instillation of WTC dust mice were exposed to daily CIH for 5 and 14 days. Endpoints analyzed were lung function, tissue histology, and oxidative stress markers.
Methods
C57BL/6J mice were exposed to chronic intermittent air (CIA) or CIH for 8 hours/day for 5 or 14 days following intratracheal instillation of WTC dust or saline (n=5). H&Estained lung sections were scored for damage by a series of measurable criteria. In order to assess epithelial cell health and proliferation sections were stained for PCNA and HO-1. These mechanistic criteria were compared to lung function results as assessed by Flexivent analysis of lung resistance and compliance.
Results
Previously we have observed a loss of barrier function and neutrophilic invasion 5 days following dust exposure and CIH, which resolved by 14 days. These criteria were also observed here and we examined lung tissue for significant structural alteration by H&E stain. No consistent damage pattern was observed in the lung tissue, which was accompanied by no alteration in PCNA staining, indicating a lack of epithelial proliferation. However, there was a significant increase in HO-1 staining through the lung following both CIH and WTC dust exposure at 5 days post injury. Functionally at 5 days CIH resulted in a significant increase in lung resistance (0.5 +/- 0.05 cm H2O/mL vs 0.72 +/- 0.2). Interestingly with dust increased resistance (0.61 +/- 0.04) irrespective of CIH. These changes were matched by a loss of compliance and a loss of PV loop area at low PEEP. These changes resolved by 14 days.
Conclusions
These results are consistent with a model in which CIH leads to increased oxidative stress within the pulmonary epithelium that results in a loss of barrier and surfactant function. However, the injury level is insufficient to produce significant epithelial proliferation and over production of surfactant. Interestingly there appears to be adaptation to the acute effects of hypoxia as function is primarily restored by 14 days. WTC dust appears to represent a separate injury stimulus that, independent of CIH, can lead to loss of epithelial function that is persistent but less severe.
Both chronic intermittent hypoxia (CIH) and particulate exposure can lead to lung injury and dysfunction. These exposures have been associated with neurocognitive and cardiovascular complications. This is a particular problem for individual’s exposed to World Trade Center (WTC) dust, who often suffer intermittent hypoxia because of obstructive sleep apnea. The current studies seek to understand how the interaction between WTC dust exposure and CIH can lead to lung injury and a loss of function. Following instillation of WTC dust mice were exposed to daily CIH for 5 and 14 days. Endpoints analyzed were lung function, tissue histology, and oxidative stress markers.
Methods
C57BL/6J mice were exposed to chronic intermittent air (CIA) or CIH for 8 hours/day for 5 or 14 days following intratracheal instillation of WTC dust or saline (n=5). H&Estained lung sections were scored for damage by a series of measurable criteria. In order to assess epithelial cell health and proliferation sections were stained for PCNA and HO-1. These mechanistic criteria were compared to lung function results as assessed by Flexivent analysis of lung resistance and compliance.
Results
Previously we have observed a loss of barrier function and neutrophilic invasion 5 days following dust exposure and CIH, which resolved by 14 days. These criteria were also observed here and we examined lung tissue for significant structural alteration by H&E stain. No consistent damage pattern was observed in the lung tissue, which was accompanied by no alteration in PCNA staining, indicating a lack of epithelial proliferation. However, there was a significant increase in HO-1 staining through the lung following both CIH and WTC dust exposure at 5 days post injury. Functionally at 5 days CIH resulted in a significant increase in lung resistance (0.5 +/- 0.05 cm H2O/mL vs 0.72 +/- 0.2). Interestingly with dust increased resistance (0.61 +/- 0.04) irrespective of CIH. These changes were matched by a loss of compliance and a loss of PV loop area at low PEEP. These changes resolved by 14 days.
Conclusions
These results are consistent with a model in which CIH leads to increased oxidative stress within the pulmonary epithelium that results in a loss of barrier and surfactant function. However, the injury level is insufficient to produce significant epithelial proliferation and over production of surfactant. Interestingly there appears to be adaptation to the acute effects of hypoxia as function is primarily restored by 14 days. WTC dust appears to represent a separate injury stimulus that, independent of CIH, can lead to loss of epithelial function that is persistent but less severe.
