Emerging evidence suggests that diseases such as IPF and COPD have observable phenotypes at the cellular and tissue levels long before the disease is clinically apparent. Thus seemingly healthy patients may have some regions of the lung affected by the same pathophysiologic processes that drive clinically apparent disease. By changing the focus of investigation from the presence or absence of disease in a given patient to the presence of absence of disease in a given region, several advantages emerge: (1) pathophysiologic mechanisms may be investigated earlier in the natural history of a disease, when interventions are more likely to be of benefit; (2) early investigation favors the discovery of distinct disease subgroups that are masked in more severe disease; and (3) a single patient may provide multiple affected and unaffected disease regions, allowing him or her to serve as their own control. Recently, advances in next-generation sequencing have made it possible for the entire transcriptome of a single cell to be analyzed. It is reasonable to believe that in the next 10 years single cell epigenome, proteome, and metabolome profiling will become routine. However, it seems less obvious how these methodologies can be employed to better understand the drivers of regional differences in lung disease. While technically difficult, studies applying high-throughput technologies to the discovery of regional differences will be invaluable to our understanding of lung disease.

To address this critical challenge, at least five technological hurdles will have to be addressed: (1) technologies such as laser capture microdissection which allow for the isolation or cells from specific areas of the lung will need to improve; (2) technologies allowing for culture of multiple cell types on a single artificial substrate (to allow for experimental manipulation of cellular “communities”) will need to emerge; (3) collaborative networks will need to emerge whereby datasets from multiple labs can be integrated; (4) bioinformatics and statistical methods capable of filtering massive “omics” data sets from multiple cell types will need to be refined; and (5) researchers with the skills necessary to distil large descriptive datasets into testable hypotheses will need to be trained. While these hurdles are great, they must be overcome in order to translate the promise of next-generation sequencing techniques into an improved understanding of the drivers of regional heterogeneity in lung disease.

Longitudinal cohorts of SCD patients, spanning childhood and adulthood, with biobanking DNA, plasma, and serum, and standardized clinical and imaging assessments will allow identification predictors of negative clinical outcomes. An NHLBI-funded national SCD clinical registry with biobanking will be necessary to validate any surrogate endpoints.

Two or more collaborating NIH Institutes could afford to fund creative projects that neither institute can afford alone.

NIH Institutes have a long history of isolation from one another. This has undoubtedly suppressed creativity and interdisciplinary research. It is inherently bureaucratic and reflects poorly on science. As an outsider I can only speculate about how to address this issue, but it would be well worth some attention at the highest levels.

The high prevalence of chronic cardiovascular and lung diseases has created burden in increasing healthcare costs and high mortality rates in the US compared to other developed countries. Even so, they remain among the most preventable health problems. A national surveillance system for chronic cardiovascular and lung diseases would enable data-driven decision-making about public health strategies for prevention, management, and cost containment.

A 2011 Institute of Medicine (IOM) report concluded that a coordinated surveillance system is needed. It proposed a framework for such a system that would integrate existing information through collective efforts of multiple stakeholders. The time is right to gain from and build upon numerous ongoing broad initiatives in biomedical Big Data, including growing health IT adoption mandated by the HITECH Act, ONCHIT efforts to achieve health IT interoperability, the NIH BD2K initiative, and the multiorganizational network participating in FDA Mini-Sentinel, HCS Collaboratory, and PCORnet, among others. The NHLBI is well-positioned to lead, develop and implement the IOM’s recommended framework and system. (IOM report - http://www.iom.edu/Reports/2011/A-Nationwide-Framework-for-Surveillance-of-Cardiovascular-and-Chronic-Lung-Diseases.aspx))
Existing data sources (i.e., population surveys, registries, cohort studies, administrative data, and vital statistics) do not individually provide nationally representative data, cannot be linked, and are not currently readily accessible to all levels of users. One potential way to build such a system is to integrate and expand existing data sources.

There is a critical need to develop uniform guidelines and handouts addressing the confusion over the proper use of medications (particularly inhalers) and equipment (i.e. oxygen). Improper use leads to diminished or no benefit, frustration, and, ultimately, even to a patient's decision to stop the treatment.

This is an issue that has been universally acknowledged for a number of years. With the help of patient focus groups, convened at the NHLBI, national pulmonological conferences, or at local venues around the country, appropriate materials can be created to benefit patients and reduce a huge burden on nation's economy due to decreased productivity and increase in hospital admissions.

may be able to target multiple diseases with new or repurposed therapies. Might narrow down the broad array of potential "high value" targets to study.

Addressing the role of chronic inflammation in chronic lung and vascular diseases will impact both the HIV population and our growing U.S. aging population. Approaches to the question could include:
1.. Causes of chronic inflammation
- Antiretroviral drugs, persistent HIV, persistence of other viruses, exogenous retroviral elements, exosomes, other epidemiologic exposures
2. Downstream mechanistic effects of chronic inflammation
- Alterations in gene regulation, alterations in oxidative stress, direct tissue damage
3. Clinical outcomes of chronic inflammation
- Lung – COPD, pulmonary HTN, cancer, interstitial lung disease, asthma.
- Vascular compartment - premature coronary and vascular disease
- Does HIV-infection itself require alterations in treatment modalities for lung disease
- Does HIV infection itself alter the outcome of chronic lung disease?
4. Therapeutic options
- Directed against the cause – i.e. antivirals.
- Immune specific targets against inflammatory mediators

The critical challenge for this question lies in the fact that complications caused by chronic inflammation such as COPD and coronary disease will by definition take years to develop. Intervention trials will take even longer. This is not like the early HIV epidemic, where complications were primarily infectious and could be seen and addressed quickly. Because of this chronic nature, it will necessary to try and establish cohorts with long term follow-up. Furthermore, it will be critical to have well defined appropriate HIV-uninfected cohorts to compare the HIV-infected population to.

Patients with chronic kidney disease tend to be undertreated (from CV perspective), underrepresented (in clinical trials) and underdiagnosed with less referral for stress testing, even though cardiovascular cause is the leading cause of death in these patients. Patients with chronic kidney disease is a growing cohort and with increase in obesity and diabetes, the prevalence is exploding exponentially. The decision as to what is the best treatment option for patients with coronary artery disease who also have kidney disease- revascularization or medical therapy-is important and can be a paradigm shift in the way we treat such patients

Randomized clinical trials are urgently needed to answer this question.

New therapies to slow CKD and to repair and regenerate failing kidneys are sorely needed to reduce health care costs and improve lives.

Our understanding of renal function and risk factors is greater than ever. Our ability to diagnose is technologically advanced. We now need to increase efforts to identify therapeutic targets and develop regenerative approaches to prevent and treat CKD.